Heteroaryl-substituted alkyne compounds and method of use

ABSTRACT

The present invention comprises a new class of compounds useful for the prophylaxis and treatment of protein kinase mediated diseases, including inflammation, cancer and related conditions. The compounds have a general Formula I 
                         
wherein A 1 , A 2 , A 3 , A 4 , R 1  and R 2  are defined herein. Accordingly, the invention also comprises pharmaceutical compositions comprising the compounds of the invention, methods for the prophylaxis and treatment of kinase mediated diseases using the compounds and compositions of the invention, and intermediates and processes useful for the preparation of compounds of the invention.

This application claims the benefit of U.S. Provisional Application No.60/620,100 filed Oct. 18, 2004, which is incorporated by referenceherein.

FIELD OF THE INVENTION

The invention generally relates to the field of pharmaceutical agentsand, more specifically, to compounds, intermediates, methods for makingthe compounds and intermediates, compositions, uses and methods formodulating protein kinases and for treating protein kinase-mediateddiseases.

BACKGROUND OF THE INVENTION

Protein kinases represent a large family of enzymes, which catalyze thephosphorylation of target protein substrates. The phosphorylation isusually a transfer reaction of a phosphate group from ATP to the proteinsubstrate. Common points of attachment for the phosphate group to theprotein substrate include, for example, a tyrosine, serine or threonineresidue. For example, protein tyrosine kinases (PTKs) are enzymes, whichcatalyze the phosphorylation of specific tyrosine residues in cellularproteins. Examples of kinases in the protein kinase family include,without limitation, ab1, Akt, bcr-ab1, Blk, Brk, Btk, c-kit, c-Met,c-src, c-fms, CDK1, CDK2, CDK3, CDK4, CDK5, CDK6, CDK7, CDK8, CDK9,CDK10, cRaf1, CSF1R, CSK, EGFR, ErbB2, ErbB3, ErbB4, Erk, Fak, fes,FGFR1, FGFR2, FGFR3, FGFR4, FGFR5, Fgr, flt-1, Fps, Frk, Fyn, Hck,IGF-1R, INS-R, Jak, KDR, Lck, Lyn, MEK, p38, PDGFR, PIK, PKC, PYK2, ros,Tie, Tie-2, TRK, Yes, and Zap70. Due to their activity in numerouscellular processes, protein kinases have emerged as importanttherapeutic targets.

Protein kinases play a central role in the regulation and maintenance ofa wide variety of cellular processes and cellular function. For example,kinase activity acts as molecular switches regulating cellproliferation, activation, and/or differentiation. Uncontrolled orexcessive kinase activity has been observed in many disease statesincluding benign and malignant proliferation disorders as well asdiseases resulting from inappropriate activation of the immune system(autoimmune disorders), allograff rejection, and graft vs host disease.In addition, endothelial cell specific receptor PTKs, such as VEGF-2 andTie-2, mediate the angiogenic process and are involved in supporting theprogression of cancers and other diseases involving uncontrolledvascularization.

Angiogenesis is the process of developing new blood vessels,particularly capillaries, from pre-existing vasculature and is anessential component of embryogenesis, normal physiological growth,repair, and tumor expansion. Angiogenesis remodels small vessels intolarger conduit vessels, a physiologically important aspect of vasculargrowth in adult tissues. Vascular growth is required for beneficialprocesses such as tissue repair, wound healing, recovery from tissueischemia and menstrual cycling.

Certain diseases and/or pathological conditions develop as a result of,or are known to be associated with, the regulation and/or deregulationof angiogenesis. For example, ocular neovascularisation such asretinopathies (including diabetic retinopathy), age-related maculardegeneration, psoriasis, hemangioblastoma, hemangioma, andarteriosclerosis have been found to be caused, in part, due the loss ofregulation and/or maintenance of vascular growth. Inflammatory diseasessuch as a rheumatoid or rheumatic inflammatory disease, and especiallyarthritis (including rheumatoid arthritis) where new capillary bloodvessels invade the joint and destroy cartilage, have been associatedwith angiogenesis. In addition, chronic inflammatory disorders such aschronic asthma, arterial or post-transplantational atherosclerosis,endometriosis, and neoplastic diseases including so-called solid tumorsand liquid tumors (for example, leukemias), have been found to be linkedto the regulation and control of angiogenesis.

The involvement of angiogenesis in major diseases has led to theidentification and development of various targets for inhibitingangiogenesis. These targets relate to various receptors, enzymes, andother proteins in the angiogenic process or cascade of events leading toangiogenesis, such as, for example, activation of endothelial cells byan angiogenic signal, synthesis and release of degradative enzymes,endothelial cell migration, proliferation of endothelial cells, andformation of capillary tubules.

One target identified in the cascade of events leading to angiogenesisis the Tie receptor family. The Tie-1 and Tie-2 receptors aresingle-transmembrane, tyrosine kinase receptors (Tie stands for tyrosinekinase receptors with immunoglobulin and EGF homology domains). Tie-2 isan endothelial cell specific receptor tyrosine kinase, which is involvedin angiogenic processes, such as vessel branching, sprouting,remodeling, maturation and stability. Tie-2 is the first mammalianreceptor for which both agonist ligand(s) (for example, Angiopoietin-1(“Ang1”) which binds to and stimulates phosphorylation and signaltransduction of Tie-2), and context dependent agonist/antagonistligand(s) (for example, Angiopoietin-2 (“Ang2”)) have been identified.Knock out and transgenic manipulation of the expression of Tie-2 and itsligands indicates that tight spacial and temporal control of Tie-2signaling is important for the proper development of newvascularization.

Biological models suggest that the stimulation of Tie-2 by the Ang1ligand is directly involved in the branching, sprouting and outgrowth ofnew vessels, and recruitment and interaction of periendothelial supportcells important in maintaining vessel integrity and inducing quiescence.The absence of Ang1 stimulation of Tie-2 or the inhibition of Tie-2autophosphorylation by Ang2, which is produced at high levels at sitesof vascular regression, may cause a loss in vascular structure andmatrix contacts resulting in endothelial death, especially in theabsence of growth/survival stimuli.

Recently, upregulation of Tie-2 expression has been found in thevascular synovial pannus of arthritic joints of humans, consistent withthe role in inappropriate neovasculariation. This finding suggests thatTie-2 plays a role in the progression of rheumatoid arthritis. Pointmutations producing constitutively activated forms of Tie-2 have beenidentified in association with human venous malformation disorders.Tie-2 inhibitors would, therefore, be useful in treating such disorders,as well as in other instances of improper neovasacularization. However,with the recent recognition of Ang3 and Ang4 as additional Tie-2 bindingligands, targeting a Tie-2 ligand-receptor interaction as ananti-angiogenic therapeutic approach is less favorable. Accordingly, aTie-2 receptor kinase inhibition approach has become the strategy ofchoice.

Angiogenesis is regarded as an absolute prerequisite for tumors thatgrow beyond a diameter of about 1-2 mm. Up to this size, oxygen andnutrients may be supplied to the tumor cells by diffusion. Every tumor,regardless of its origin and its cause, is thus dependent onangiogenesis for its growth after it has reached a certain size.

Three principal mechanisms play an important part in the activity ofangiogenesis inhibitors against tumors: 1) Inhibition of the growth ofvessels, especially capillaries, into vascular resting tumors, with theresult that there is no net tumor growth owing to the balance that isachieved between cell death and proliferation; 2) Prevention of themigration of tumor cells owing to the absence of blood flow to and fromtumors; and 3) Inhibition of endothelial cell proliferation, thusavoiding the paracrine growth-stimulating effect exerted on thesurrounding tissue by the endothelial cells which normally line thevessels. See R. Connell and J. Beebe, Exp. Opin. Ther. Patents,11:77-114 (2001).

The inhibition of vascular growth in this context has also shownbeneficial effects in preclinical animal models. For example, inhibitionof angiogenesis by blocking vascular endothelial growth factor or itsreceptor has resulted in inhibition of tumor growth and in retinopathy.Also, the development of pathological pannus tissue in rheumatoidarthritis involves angiogenesis and might be blocked by inhibitors ofangiogenesis.

The ability to stimulate vascular growth has potential utility fortreatment of ischemia-induced pathologies such as myocardial infarction,coronary artery disease, peripheral vascular disease, and stroke. Thesprouting of new vessels and/or the expansion of small vessels inischemic tissues prevents ischemic tissue death and induces tissuerepair. Regulating angiogenesis by inhibiting certain recognizedpathways in this process would, therefore, be useful in treatingdiseases, such as ocular neovascularization, including retinopathy,age-related macular degeneration, psoriasis, hemangioblastoma,hemangioma, arteriosclerosis, inflammatory disease rheumatoid arthritis,chronic inflammatory disorders such as chronic asthma, arterial orpost-transplantational atherosclerosis, endometriosis, and neoplasticdiseases such as leukemias, otherwise known to be associated withderegulated angiogenesis. Treatment of malaria and related viraldiseases may also be mediated by HGF and cMet.

Recent work on the relationship between inhibition of angiogenesis andthe suppression or reversion of tumor progression shows great promise inthe treatment of cancer (Nature, 390:404-407 (1997)), especially the useof multiple angiogenesis inhibitors compared to the effect of a singleinhibitor.

Non-receptor tyrosine kinases represent a collection of cellularenzymes, which lack extracellular activity and transmembrane sequences.Examples of non-receptor tyrosine kinases identified include overtwenty-four individual kinases, comprising eleven (11) subfamilies (Src,Frk, Btk, Csk, Abl, Zap70, Fes/Fps, Fak, jak, Ack, and LIMK). Src isthought to be the largest family including Src, Lck, Fyn(B), Fyn(T),Lyn, Yes, Hck, Fgr and Blk (for review see: Bolen, J B, and Brugge, J SAnnu. Rev. Immunol, 15, 371, 1997). The Src subfamily has been linked tooncogenesis and immune responses (See Bohlen, Oncogene, 8:2025-2031,1993). These kinases have also been found to be involved in cellularsignaling pathways in numerous pathogenic conditions, including cancer,psoriasis, and other hyper-proliferative disorders or hyper-immuneresponses. Thus, it would be useful to inhibit the activity ofnon-receptor kinases as well.

Members of the Src-family of tyrosine kinases, in particular, have beenshown to be important in cell signal transduction as it relates toinflammatory response and inflammation-related conditions. Genedisruption studies suggest that inhibition of some members of the srcfamily of kinases would potentially lead to a therapeutic benefit.Src(−/−) mice have abnormalities in bone remodeling or osteopetrosis(Soriano, P. Cell 1991, 64, 693), suggesting that inhibition of thiskinase might be useful in diseases of bone resorption, such asosteoporosis. Lck(−/−) mice have defects in T cell maturation andactivation (Anderson, S J et al. Adv. Immunol. 1994, 56, 151),suggesting that inhibition of this kinase might be useful in diseases ofT cell mediated inflammation. In addition, human patients have beenidentified with mutations affecting Lck kinase activity (Goldman, F D etal. J. Clin. Invest. 1998, 102, 421). These patients suffer from asevere combined immunodeficiency disorder (SCID).

T cells play a pivotal role in the regulation of immune responses andare important for establishing immunity to pathogens. In addition, Tcells are often activated during inflammatory autoimmune diseases, suchas rheumatoid arthritis, inflammatory bowel disease, type I diabetes,multiple sclerosis, Sjogren's disease, myasthenia gravis, psoriasis, andlupus. T cell activation is also an important component of transplantrejection, allergic reactions, and asthma.

T cells are activated by specific antigens through the T cell receptor(TCR), which is expressed on the cell surface. This activation triggersa series of intracellular signaling cascades mediated by enzymesexpressed within the cell (Kane, L P et al. Current Opinion in Immunol.12, 242, 2000). These cascades lead to gene regulation events thatresult in the production of cytokines, like interleukin-2 (IL-2). IL-2is a necessary cytokine in T cell activation, leading to proliferationand amplification of specific immune responses.

Src-family kinases are also important for signaling downstream of otherimmune cell receptors. Fyn, like Lck, is involved in TCR signaling in Tcells (Appleby, M W et al. Cell, 70, 751, 1992). Hck and Fgr areinvolved in Fcγ receptor signaling leading to neutrophil activation(Vicentini, L. et al. J. Immunol. 2002, 168, 6446). Lyn and Src alsoparticipate in Fcγ receptor signaling leading to release of histamineand other allergic mediators (Turner, H. and Kinet, J-P Nature 1999,402, B24). These-findings suggest that Src family kinase inhibitors maybe useful in treating allergic diseases and asthma.

Src kinases are also activated in tumors including sarcoma, melanoma,breast, and colon cancers suggesting that Src kinase inhibitors may beuseful anti-cancer agents (Abram, C L and Courtneidge, S A Exp. CellRes., 254, 1, 2000). Src kinase inhibitors have also been reported to beeffective in an animal model of cerebral ischemia (R. Paul et al. NatureMedicine, 7, 222, 2001), suggesting that Src kinase inhibitors may beeffective at limiting brain damage following stroke.

Many classes of compounds have been disclosed to modulate or, morespecifically, inhibit kinase activity for use to treat kinase-relatedconditions or other disorders. For example, the PCT publication, WO01/81311, published on Nov. 1, 2001, describes substituted benzoic acidamides and use thereof for the inhibition of angiogenisis; U.S. Pat. No.6,440,965, issued Aug. 27, 2002, describes substituted pyrimidinederivatives and their use in the treatment of neurodegenerative orneurological disorders of the central nervous system; PCT publication,WO 02/08205, published on Jan. 13, 2001, describes substitutedpyrimidines having neurotrophic activity; PCT publication, WO 03/014111,published on Feb. 20, 2003, describes arylpiperazines andarylpiperidines and their use as metalloproteinase inhibiting agents;PCT publication, WO 03/024448, published on Mar. 27, 2003, describescompounds as inhibitors of histone deacetylase enzymatic activity; PCTpublication, WO 04/058776, published on Jul. 15, 2004, describescompounds which possess anti-angiogenic activity; and PCT publication,WO 04/062601, published on Jul. 29, 2004, describes compounds asanti-bacterial agents for generally treating infections caused bygram-negative bacteria.

BRIEF DESCRIPTION OF THE INVENTION

The present invention provides new heteroaryl-substituted alkynecompounds useful in treating pathological conditions and/or diseasestates related to kinase activity. Particularly, the compounds areuseful for treating various diseases, such as cancer, inflammation andrelated disorders and conditions including rheumatoid arthritis. Thecompounds are useful by virtue of their ability to regulate activeangiogenesis, cell-signal transduction and related pathways, forexample, through kinase modulation. The compounds provided by theinvention, including stereoisomers, tautomers, solvates,pharmaceutically acceptable salts, derivatives or prodrugs thereof, aredefined by general Formula I

wherein A¹, A², A³, A⁴, R¹ and R² are as described below.

The invention also provides procedures for making compounds of FormulaI, as well as intermediates useful in such procedures.

The compounds provided by the invention are capable of modulatingvarious kinase activity. For example, in one embodiment, the compoundsare capable of modulating one or both of Tie-2 or Lck kinase enzymes. Inparticular, the compounds are capable of inhibiting the activity ofTie-2, and Lck.

To this end, the invention further provides for the use of thesecompounds for therapeutic, prophylactic, acute and/or chronic treatmentof Tie-2 and/or Lck kinase mediated diseases, such as those describedherein. For example, the invention provides the use and preparation of amedicament, containing one or more of the compounds, useful toattenuate, alleviate, or treat disorders through inhibition of Tie-2and/or Lck. These compounds are also useful in the treatment of anangiogenesis- or T-cell activation- or proliferation-mediated disease orcondition. Accordingly, these compounds are useful in the manufacture ofanti-cancer and anti-inflammation medicaments. In one embodiment, theinvention provides a pharmaceutical composition comprising an effectivedosage amount of a compound of Formula I in association with a least onepharmaceutically acceptable carrier, adjuvant or diluent.

Further, the invention provides a method of treating kinase mediateddisorders, such as treating angiogenesis related or T-cell activationrelated disorders in a subject inflicted with, or susceptible to, suchdisorder. The method comprises administering to the subject an effectivedosage amount of a compound of Formula I. In other embodiments, theinvention provides methods of reducing tumor size, blood flow to andfrom a tumor, and treating or alleviating various inflammatoryresponses, including arthritis, organ transplantation or rejection, andmany others as described herein.

The foregoing merely summarizes certain aspects of the invention and isnot intended, nor should it be construed, as limiting the invention inany way. All patents and other publications recited herein are herebyincorporated by reference in their entirety.

DETAILED DESCRIPTION OF THE INVENTION

In one embodiment of the invention, heteroaryl-substituted alkynecompounds useful for treating angiogenesis- and/or T-cellproliferation-related disorders, including cancer and inflammation areprovided. The compounds, including stereoisomers, tautomers, solvates,pharmaceutically acceptable salts, derivatives or prodrugs thereof, aredefined by general Formula I:

wherein

A¹ is CR³ or N;

A² is CR⁴ or N;

A³ is CR⁵ or N;

A⁴ is CR⁶ or N;

provided that at least one of A¹, A², A³ and A⁴ is N and no more thanthree of A¹, A², A³ and A⁴ are N;

R¹ is NR⁷R⁷, NR⁷R⁸, SR⁷, OR⁸; SR⁸, C(O)R⁷, OC(O)R⁷, COOR⁷, C(O)R⁸,OC(O)R⁸, COOR⁸, C(O)NR⁷R⁷, C(S)NR⁷R⁷, NR⁷C(O)R⁷, NR⁷C(S)R⁷,NR⁷C(O)NR⁷R⁷, NR⁷C(S)NR⁷R⁷, NR⁷(COOR⁷), OC(O)NR⁷, C(O)NR⁷R⁸, C(S)NR⁷R⁸,NR⁷C(O)R⁸, NR⁷C(S)R⁸, NR⁷C(O)NR⁷R⁸, NR⁷C(S)NR⁷R⁸, NR⁷(COOR⁸),OC(O)NR⁷R⁸, S(O)₂NR⁷R⁷, NR⁷S(O)₂NR⁷R⁷, NR⁷S(O)₂R⁷, S(O)₂R⁸, S(O)₂NR⁷R⁸,NR⁷S(O)₂NR⁷R⁸ or NR⁷S(O)₂R⁸;

R² is a partially or fully saturated or unsaturated 5-8 memberedmonocyclic, 6-12 membered bicyclic, or 7-14 membered tricyclic ringsystem, said ring system formed of carbon atoms optionally including 1-3heteroatoms if monocyclic, 1-6 heteroatoms if bicyclic, or 1-9heteroatoms if tricyclic, said heteroatoms selected from O, N, or S,wherein said ring system is substituted independently with one or moresubstituents of R¹⁰, R¹¹, R¹⁵, NR¹⁰R¹⁰, NR¹⁰R¹¹, OR¹⁰, SR¹⁰, OR¹¹, SR¹¹,C(O)R¹⁰, C(S)R¹⁰, C(NCN)R¹⁰, C(O)R¹¹, C(S)R¹¹, C(NCN)R¹¹, C(O)C(O)R¹⁰,OC(O)R¹⁰, COOR¹⁰, C(O)SR¹⁰, C(O)C(O)R¹¹, OC(O)R¹¹, COOR¹¹, C(O)SR¹¹,C(O)NR¹⁰R¹⁰, C(S)NR¹⁰R¹⁰, C(O)NR¹⁰R¹¹, C(S)NR¹⁰R¹¹, OC(O)NR¹⁰R¹¹,NR¹⁰C(O)R¹⁰, NR¹⁰C(O)R¹¹, NR¹⁰C(S)R¹⁰, NR¹⁰C(S)R¹¹, NR¹⁰C(O)NR¹⁰R¹⁰,NR¹⁰C(O)NR¹⁰R¹¹, NR¹⁰C(S)NR¹⁰R¹⁰, NR¹⁰C(S)NR¹⁰R¹¹, NR¹⁰(COOR¹⁰),NR¹⁰(COOR¹¹), NR¹⁰C(O)C(O)R¹⁰, NR¹⁰C(O)C(O)R¹¹, NR¹⁰C(O)C(O)NR¹⁰R¹¹,S(O)₂R¹⁰, S(O)₂R¹¹, S(O)₂NR¹⁰R¹⁰, S(O)₂NR¹⁰R¹¹, NR¹⁰S(O)₂NR¹⁰R¹¹,NR¹⁰S(O)₂R¹⁰ or NR¹⁰S(O)₂R¹¹, provided that at least one substituent onsaid ring system is C(O)₂R¹⁰, C(O)₂R¹¹, C(O)C(O)R¹⁰, OC(O)R¹⁰, COOR¹⁰,C(O)SR¹⁰, C(O)C(O)R¹¹, OC(O)R¹¹, COOR¹¹, C(O)SR¹¹, C(O)NR¹⁰R¹⁰,C(S)NR¹⁰R¹⁰, C(O)NR¹⁰R¹¹, C(S)NR¹⁰R¹¹, OC(O)NR¹⁰R¹¹, NR¹⁰R¹¹,NR¹⁰C(O)R¹⁰, NR¹⁰C(O)R¹¹, NR¹⁰C(S)R¹⁰, NR¹⁰C(S)R¹¹, NR¹⁰C(O)NR¹⁰R¹⁰,NR¹⁰C(O)NR¹⁰R¹¹, NR¹⁰C(S)NR¹⁰R¹⁰, NR¹⁰C(S)NR¹⁰R¹¹, NR¹⁰(COOR¹⁰),NR¹⁰(COOR¹¹), NR¹⁰C(O)C(O)R¹⁰, NR¹⁰C(O)C(O)R¹¹, NR¹⁰C(O)C(O)NR¹⁰R¹¹,S(O)₂R¹⁰, S(O)₂R¹¹, S(O)₂NR¹⁰R¹⁰, S(O)₂NR¹⁰R¹¹, NR¹⁰S(O)₂NR¹⁰R¹¹,NR¹⁰S(O)₂R¹⁰ or NR¹⁰S(O)₂R¹¹;

R³ is H, halo, haloalkyl, NO₂, CN, OR⁷, SR⁷, NR⁷R⁷, NR⁷R⁸, C(O)R⁷,COOR⁷, C(O)NR⁷R⁷, C(O)NR⁷R⁸, NR⁷C(O)NR⁷R⁷, NR⁷C(O)NR⁷R⁸, OC(O)NR⁷R⁸,S(O)₂R⁷, S(O)₂NR⁷R⁷, S(O)₂NR⁷R⁸, NR⁷S(O)₂R⁷, NR⁷S(O)₂R⁸, C₁₋₁₀-alkyl,C₂₋₁₀-alkenyl, C₂₋₁₀-alkynyl, C₃₋₁₀-cycloalkyl or C₄₋₁₀-cycloalkenyl,each of the C₁₋₁₀-alkyl, C₂₋₁₀-alkenyl, C₂₋₁₀-alkynyl, C₃₋₁₀-cycloalkyland C₄₋₁₀-cycloalkenyl optionally comprising 1-4 heteroatoms selectedfrom N, O and S and optionally substituted with 1-5 substituents of R⁸or R⁹;

alternatively R¹ and R³ taken together with the atoms to which they areattached form a partially or fully unsaturated 5- or 6-membered ring ofcarbon atoms optionally including 1-3 heteroatoms selected from O, N, orS, and the ring optionally substituted independently with 1-5substituents of R⁸ or R⁹;

R⁴ is H, halo, haloalkyl, NO₂, CN, NR⁷R⁷, OR⁷; SR⁷, C(O)R⁷, C₁₋₁₀-alkyl,C₂₋₁₀-alkenyl, C₂₋₁₀-alkynyl or C₃₋₁₀-cycloalkyl, each of theC₁₋₁₀-alkyl, C₂₋₁₀-alkenyl, C₂₋₁₀-alkynyl and C₃₋₁₀-cycloalkyloptionally comprising 1-4 heteroatoms selected from N, O and S andoptionally substituted with 1-5 substituents of R⁹;

alternatively R³ and R⁴ taken together with the atoms to which they areattached form a partially or fully unsaturated 5- or 6-membered ring ofcarbon atoms optionally including 1-3 heteroatoms selected from O, N, orS, and the ring optionally substituted independently with 1-3substituents of R⁸ or R⁹

R⁵ is H, halo, haloalkyl, NO₂, CN, NR⁷R⁷, OR⁷; SR⁷, C(O)R⁷, C₁₋₁₀-alkyl,C₂₋₁₀-alkenyl, C₂₋₁₀-alkynyl or C₃₋₁₀-cycloalkyl, each of theC₁₋₁₀-alkyl, C₂₋₁₀-alkenyl, C₂₋₁₀-alkynyl and C₃₋₁₀-cycloalkyloptionally comprising 1-4 heteroatoms selected from N, O and S andoptionally substituted with 1-5 substituents of R⁹;

R⁶ is H, halo, haloalkyl, NO₂, CN, SR⁷, OR⁷, C(O)R⁷, COOR⁷, OC(O)R⁷,NR⁷R⁷, NR⁷R⁸, C(O)NR⁷R⁷, C(O)NR⁷R⁸, NR⁷C(O)R⁷, NR⁷C(O)NR⁷R⁸, S(O)NR⁷R⁸,S(O)₂NR⁷R⁸, NR⁷S(O)NR⁷R⁸, NR⁷C₁₋₁₀-alkyl, C₂₋₁₀-alkenyl, C₂₋₁₀-alkynyl,C₃₋₁₀-cycloalkyl or C₄₋₁₀-cycloalkenyl, each of the C₁₋₁₀-alkyl,C₂₋₁₀-alkenyl, C₂₋₁₀-alkynyl, C₃₋₁₀-cycloalkyl and C₄₋₁₀-cycloalkenyloptionally comprising 1-4 heteroatoms selected from N, O and S andoptionally substituted with 1-5 substituents of R⁸ or R⁹;

alternatively R¹ and R⁶ taken together with the atoms to which they areattached form a partially or fully unsaturated 5- or 6-membered ring ofcarbon atoms optionally including 1-3 heteroatoms selected from O, N, orS, and the ring optionally substituted independently with 1-5substituents of R⁸ or R⁹;

alternatively R⁵ and R⁶ taken together with the atoms to which they areattached form a partially or fully unsaturated 5- or 6-membered ring ofcarbon atoms optionally including 1-3 heteroatoms selected from O, N, orS, and the ring optionally substituted independently with 1-3substituents of R⁸ or R⁹;

R⁷ is H, C₁₋₁₀-alkyl, C₂₋₁₀-alkenyl, C₂₋₁₀-alkynyl, C₃₋₁₀-cycloalkyl orC₄₋₁₀-cycloalkenyl, each of the C₁₋₁₀-alkyl, C₂₋₁₀-alkenyl,C₂₋₁₀-alkynyl, C₃₋₁₀-cycloalkyl and C₄₋₁₀-cycloalkenyl optionallycomprising 1-4 heteroatoms selected from N, O and S and optionallysubstituted with 1-5 substituents of NR⁸R⁹, NR⁹R⁹, OR⁸, SR⁸, OR⁹, SR⁹,C(O)R⁸, OC(O)R⁸, COOR⁸, C(O)R⁹, OC(O)R⁹, COOR⁹, C(O)NR⁸R⁹, C(O)NR⁹R⁹,NR⁹C(O)R⁸, NR⁹C(O)R⁹, NR⁹C(O)NR⁸R⁹, NR⁹C(O)NR⁹R⁹, NR⁹(COOR⁸),NR⁹(COOR⁹), OC(O)NR⁸R⁹, OC(O)NR⁹R⁹, S(O)₂R⁸, S(O)₂NR⁸R⁹, S(O)₂R⁹,S(O)₂NR⁹R⁹, NR⁹S(O)₂NR⁸R⁹, NR⁹S(O)₂NR⁹R⁹, NR⁹S(O)₂R⁸, NR⁹S(O)₂R⁹, R⁸ orR⁹;

R⁸ is a partially or fully saturated or unsaturated 5-8 memberedmonocyclic, 6-12 membered bicyclic, or 7-14 membered tricyclic ringsystem, said ring system formed of carbon atoms optionally including 1-3heteroatoms if monocyclic, 1-6 heteroatoms if bicyclic, or 1-9heteroatoms if tricyclic, said heteroatoms selected from O, N, or S, andwherein said ring system is optionally substituted independently with1-5 substituents of R⁹, oxo, NR⁹R⁹, OR⁹; SR⁹, C(O)R⁹ or a partially orfully saturated or unsaturated 5-6 membered ring of carbon atomsoptionally including 1-3 heteroatoms selected from O, N, or S, andoptionally substituted independently with 1-5 substituents of R⁹;

alternatively, R⁷ and R⁸ taken together form a saturated or partially orfully unsaturated 5-6 membered ring of carbon atoms optionally including1-3 heteroatoms selected from O, N, or S, and said ring optionallysubstituted independently with 1-5 substituents of R⁹;

R⁹ is H, halo, haloalkyl, CN, OH, NO₂, NH₂, acetyl, C₁₋₁₀-alkyl,C₂₋₁₀-alkenyl, C₂₋₁₀-alkynyl, C₃₋₁₀-cycloalkyl, C₄₋₁₀-cycloalkenyl,C₁₋₁₀-alkylamino-, C₁₋₁₀-dialkylamino-, C₁₋₁₀-alkoxyl, C₁₋₁₀-thioalkoxylor a saturated or partially or fully unsaturated 5-8 membered monocyclicor a 6-12 membered bicyclic, said ring system formed of carbon atomsoptionally including 1-3 heteroatoms if monocyclic or 1-6 heteroatoms ifbicyclic, said heteroatoms selected from O, N, or S, wherein each of theC₁₋₁₀-alkyl, C₂₋₁₀-alkenyl, C₂₋₁₀-alkynyl, C₃₋₁₀-cycloalkyl,C₄₋₁₀-cycloalkenyl, C₁₋₁₀-alkylamino-, C₁₋₁₀-dialkylamino-,C₁₋₁₀-alkoxyl, C₁₋₁₀-thioalkoxyl and ring of said ring system isoptionally substituted independently with 1-5 substituents of halo,haloalkyl, CN, NO₂, NH₂, OH, oxo, methyl, methoxyl, ethyl, ethoxyl,propyl, propoxyl, isopropyl, cyclopropyl, butyl, isobutyl, tert-butyl,methylamine, dimethylamine, ethylamine, diethylamine, propylamine,isopropylamine, dipropylamine, diisopropylamine, benzyl or phenyl;

R¹⁰ is H, halo, haloalkyl, CN, NO₂, C₁₋₁₀-alkyl, C₂₋₁₀-alkenyl,C₂₋₁₀-alkynyl, C₃₋₁₀-cycloalkyl or C₄₋₁₀-cycloalkenyl, each of theC₁₋₁₀-alkyl, C₂₋₁₀-alkenyl, C₂₋₁₀-alkynyl, C₃₋₁₀-cycloalkyl andC₄₋₁₀-cycloalkenyl optionally comprising 1-4 heteroatoms selected fromN, O and S and optionally substituted with 1-5 substituents of R¹¹, R¹²or R¹⁶, NR¹¹R¹², NR¹²R¹², OR¹¹, SR¹¹, OR¹², SR¹², C(O)R¹¹, OC(O)R¹¹,COOR¹¹, C(O)R¹², OC(O)R¹², COOR¹², C(O)NR¹¹R¹², NR¹²C(O)R¹¹,C(O)NR¹²R¹², NR¹²C(O)R¹², NR¹²C(O)NR¹¹R¹², NR¹²C(O)NR¹²R¹²,NR¹²(COOR¹¹), NR¹²(COOR¹²), OC(O)NR¹¹R¹², OC(O)NR¹²R¹², S(O)₂R¹¹,S(O)₂R¹², S(O)₂NR¹¹R¹², S(O)₂NR¹²R¹², NR¹²S(O)₂NR¹¹R¹²,NR¹²S(O)₂NR¹²R¹², NR¹²S(O)₂R¹¹, NR¹²S(O)₂R¹², NR¹²S(O)₂R¹¹ orNR¹²S(O)₂R¹²;

R¹¹ is a partially or fully saturated or unsaturated 5-8 memberedmonocyclic, 6-12 membered bicyclic, or 7-14 membered tricyclic ringsystem, said ring system formed of carbon atoms optionally including 1-3heteroatoms if monocyclic, 1-6 heteroatoms if bicyclic, or 1-9heteroatoms if tricyclic, said heteroatoms selected from O, N, or S, andwherein each ring of said ring system is optionally substitutedindependently with 1-5 substituents of R¹², R¹³, R¹⁴ or R¹⁶;

alternatively, R¹⁰ and R¹¹ taken together form a partially or fullysaturated or unsaturated 5-6 membered ring of carbon atoms optionallyincluding 1-3 heteroatoms selected from O, N, or S, and the ringoptionally substituted independently with 1-5 substituents of R¹², R¹³,R¹⁴ or R¹⁶;

R¹² is H, C₁₋₁₀-alkyl, C₂₋₁₀-alkenyl, C₂₋₁₀-alkynyl, C₃₋₁₀-cycloalkyl,C₄₋₁₀-cycloalkenyl, C₁₋₁₀-alkylamino-, C₁₋₁₀-dialkylamino-,C₁₋₁₀-alkoxyl or C₁₋₁₀-thioalkyl, each of which is optionallysubstituted independently with 1-5 substituents of R¹³, R¹⁴, R¹⁵ or R¹⁶;

R¹³ is NR¹⁴R¹⁵, NR¹⁵R¹⁵, OR¹⁴; SR¹⁴, OR¹⁵; SR¹⁵, C(O)R¹⁴, OC(O)R¹⁴,COOR¹⁴, C(O)R¹⁵, OC(O)R¹⁵, COOR¹⁵, C(O)NR¹⁴R¹⁵, C(O)NR¹⁵R¹⁵,NR¹⁴C(O)R¹⁴, NR¹⁵C(O)R¹⁴, NR¹⁴C(O)R¹⁵, NR¹⁵C(O)R¹⁵, NR¹⁵C(O)NR¹⁴R¹⁵,NR¹⁵C(O)NR¹⁵R¹⁵, NR¹⁵(COOR¹⁴), NR¹⁵(COOR¹⁵), OC(O)NR¹⁴R¹⁵, OC(O)NR¹⁵R¹⁵,S(O)₂R¹⁴, S(O)₂R¹⁵, S(O)₂NR¹⁴R¹⁵, S(O)₂NR¹⁵R¹⁵, NR¹⁴S(O)₂NR¹⁴R¹⁵,NR¹⁵S(O)₂NR¹⁵R¹⁵, NR¹⁴S(O)₂R¹⁴ or NR¹⁵S(O)₂R¹⁵;

R¹⁴ is a partially or fully saturated or unsaturated 5-8 membered or asaturated or partially or fully unsaturated 5-8 membered monocyclic,6-12 membered bicyclic, or 7-14 membered tricyclic ring system, saidring system formed of carbon atoms optionally including 1-3 heteroatomsif monocyclic, 1-6 heteroatoms if bicyclic, or 1-9 heteroatoms iftricyclic, said heteroatoms selected from O, N, or S, and wherein saidring system is optionally substituted independently with 1-5substituents of R¹⁵ or R¹⁶;

R¹⁵ is H or C₁₋₁₀-alkyl, C₂₋₁₀-alkenyl, C₂₋₁₀-alkynyl, C₃₋₁₀-cycloalkyl,C₄₋₁₀-cycloalkenyl, C₁₋₁₀-alkylamino-, C₁₋₁₀-dialkylamino-,C₁₋₁₀-alkoxyl or C₁₋₁₀-thioalkoxyl, each of which is optionallysubstituted independently with 1-5 substituents of R¹⁶;

R¹⁶ is H, halo, haloalkyl, CN, OH, NO₂, NH₂, OH, methyl, methoxyl,ethyl, ethoxyl, propyl, propoxyl, isopropyl, cyclopropyl, butyl,isobutyl, tert-butyl, methylamino, dimethylamino, ethylamino,diethylamino, isopropylamino, oxo, acetyl, benzyl, phenyl, cyclopropyl,cyclobutyl or a partially or fully saturated or unsaturated 5-8 memberedmonocyclic or 6-12 membered bicyclic ring system, said ring systemformed of carbon atoms optionally including 1-3 heteroatoms ifmonocyclic or 1-6 heteroatoms if bicyclic, said heteroatoms selectedfrom O, N, or S, and optionally substituted independently with 1-5substituents of halo, haloalkyl, CN, NO₂, NH₂, OH, methyl, methoxyl,ethyl, ethoxyl, propyl, propoxyl, isopropyl, cyclopropyl, butyl,isobutyl, tert-butyl, methylamino, dimethylamino, ethylamino,diethylamino, isopropylamino, benzyl or phenyl;

and provided that (1) when said at least one substituent on said R² ringsystem is C(O)NR¹⁰R¹⁰ or C(O)NR¹⁰R¹¹, then R¹⁰ and R¹¹, independently,are not —CH₂-L-Q or —C(C₁₋₆alkyl)(C₁₋₆alkyl)-L-Q, wherein L is —O—,—NH—, —NHC(O)—, —NHC(O)N—, —NHC(═NH)N— or —CO₂— and Q is H, substitutedor unsubstituted C₁₋₆alkyl, substituted or unsubstituted aryl,substituted or unsubstituted heterocyclyl, substituted or unsubstitutedheteraryl or C₁₋₆alkyl substituted with aryl, heterocyclyl orheteroaryl; or

(2) when said R² is a phenyl ring substituted with C(O)NR¹⁰R¹⁰ orC(O)NR¹⁰R¹¹ meta to the alkynyl group of Formula I, then either (a) R¹is not halogen, C₁₋₆alkyl, C₁₋₆alkoxyl or hydroxyl or (b) where R¹ andR³ taken together with the atoms to which they are attached form apartially or fully unsaturated 5- or 6-membered ring of carbon atomsoptionally including 1-3 heteroatoms selected from O, N, or S, said ringis not substituted with halogen, C₁₋₆alkyl, C₁₋₆alkoxyl or hydroxylsubstituents.

In another embodiment, the compounds of Formula I include N as A¹, inconjunction with any of the above or below embodiments.

In another embodiment, the compounds of Formula I include N as A⁴, inconjunction with any of the above or below embodiments.

In another embodiment, the compounds of Formula I include N,independently, as both A¹ and A⁴, in conjunction with any of the aboveor below embodiments.

In another embodiment, the compounds of Formula I include compoundswherein A¹ is N, A² is CR⁴, A³ is CR⁵ and A⁴ is CR⁶, in conjunction withany of the above or below embodiments.

In another embodiment, the compounds of Formula I include compoundswherein A¹ is CR³, A² is CR⁴, A³ is CR⁵ and A⁴ is N, in conjunction withany of the above or below embodiments.

In another embodiment, the compounds of Formula I include compoundswherein each of A² and A³, independently, is N, A¹ is CR³ and A⁴ is CR⁶,in conjunction with any of the above or below embodiments.

In another embodiment, the compounds of Formula I include compoundswherein each of A¹ and A², independently, is N, A³ is CR⁵ and A⁴ is CR⁶,in conjunction with any of the above or below embodiments.

In another embodiment, the compounds of Formula I include compoundswherein each of A¹ and A⁴, independently, is N, A² is CR⁴ and A³ is CR⁵,in conjunction with any of the above or below embodiments.

In another embodiment, the compounds of Formula I include N as A¹, N asA⁴, and a substituted 5-6 membered monocyclic aryl or heteroaryl ringsystem, or a 8-12 membered bicyclic aryl or heteroaryl ring system, saidring system including 1-3 heteroatoms if monocyclic or 1-6 heteroatomsif bicyclic, said heteroatoms selected from O, N and S as R³, inconjunction with any of the above or below embodiments.

In another embodiment, the compounds of Formula I include phenyl,naphthyl, pyridyl, pyrimidinyl, triazinyl, quinolinyl, isoquinolinyl,quinazolinyl, isoquinazolinyl, thiophenyl, furyl, pyrrolyl, imidazolyl,triazolyl, thiazolyl, oxazolyl, isoxazolyl, isothiazolyl, indolyl,isoindolyl, benzofuranyl, dihydrobenzofuranyl, benzothiophenyl orbenzimidazolyl as the substituted ring system of R² in the embodimentabove, in conjunction with any of the above or below embodiments.

In another embodiment, the compounds of Formula I in the embodimentimmediately above include C(O)R¹⁰, COOR¹⁰, C(O)R¹¹, COOR¹¹, C(O)NR¹⁰R¹⁰,C(S)NR¹⁰R¹⁰, C(O)NR¹⁰R¹¹, C(S)NR¹⁰R¹¹, NR¹⁰R¹¹, NR¹⁰C(O)R¹⁰,NR¹⁰C(S)R¹⁰, NR¹⁰C(O)R¹¹, NR¹⁰C(S)R¹¹, NR¹⁰C(O)NR¹⁰R¹⁰, NR¹⁰C(O)NR¹⁰R¹¹,NR¹⁰C(S)NR¹⁰R¹⁰, NR¹⁰C(S)NR¹⁰R¹¹, NR¹⁰(COOR¹⁰), NR¹⁰(COOR¹¹),S(O)₂NR¹⁰R¹⁰, S(O)₂NR¹⁰R¹¹, NR¹⁰S(O)₂NR¹⁰R¹¹, NR¹⁰S(O)₂R¹⁰ orNR¹⁰S(O)₂R¹¹ as a substituent on R², taken in conjunction with any ofthe above or below embodiments.

In another embodiment, the compounds are generally defined by Formula Iabove, wherein

A¹ and A⁴, independently, are N;

A² is CR⁴;

A³ is CR⁵;

R¹ is NR⁷R⁷, NR⁷R⁸, SR⁷, OR⁸, SR⁸, C(O)R⁷, OC(O)R⁷, COOR⁷, C(O)R⁸,OC(O)R⁸, COOR⁸, C(O)NR⁷R⁷, C(S)NR⁷R⁷, NR⁷C(O)R⁷, NR⁷C(S)R⁷,NR⁷C(O)NR⁷R⁷, NR⁷C(S)NR⁷R⁷, NR⁷(COOR⁷), OC(O)NR⁷R⁷, C(O)NR⁷R⁸,C(S)NR⁷R⁸, NR⁷C(O)R⁸, NR⁷C(S)R⁸, NR⁷C(O)NR⁷R⁸, NR⁷C(S)NR⁷R⁸, NR⁷(COOR⁸),OC(O)NR⁷R⁸, S(O)₂R⁷, S(O)₂NR⁷R⁷, NR⁷S(O)₂NR⁷R⁷, NR⁷S(O)₂R⁷, S(O)₂R⁸,S(O)₂NR⁷R⁸, NR⁷S(O)₂NR⁷R⁸ or NR⁷S(O)₂R⁸;

R² is a phenyl, naphthyl, pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl,triazinyl, quinolinyl, isoquinolinyl, quinazolinyl, isoquinazolinyl,phthalazinyl, aza-phthalazinyl, thiophenyl, furyl, pyrrolyl, imidazolyl,pyrazolyl, triazolyl, thiazolyl, thiadiazolyl, oxazolyl, isoxazolyl,oxadiazolyl, isothiazolyl, indolyl, isoindolyl, benzofuranyl,dihydrobenzofuranyl, benzothiophenyl or benzimidazolyl ring system, saidring system substituted independently with 1-5 substituents of R¹⁰, R¹¹,R¹⁵, NR¹⁰R¹⁰, NR¹⁰R¹¹, OR¹⁰, SR¹⁰, OR¹¹, SR¹¹, C(O)R¹⁰, C(S)R¹⁰,C(NCN)R¹⁰, C(O)R¹¹, C(S)R¹¹, C(NCN)R¹¹, C(O)C(O)R¹⁰, OC(O)R¹⁰, COOR¹⁰,C(O)SR¹⁰, C(O)C(O)R¹¹, OC(O)R¹¹, COOR¹¹, C(O)SR¹¹, C(O)NR¹⁰R¹⁰,C(S)NR¹⁰R¹⁰, C(O)NR¹⁰R¹¹, C(S)NR¹⁰R¹¹, OC(O)NR¹⁰R¹¹, NR¹⁰C(O)R¹⁰,NR¹⁰C(O)R¹¹, NR¹⁰C(S)R¹⁰, NR¹⁰C(S)R¹¹, NR¹⁰C(O)NR¹⁰R¹⁰, NR¹⁰C(O)NR¹⁰R¹¹,NR¹⁰C(S)NR¹⁰R¹⁰, NR¹⁰C(S)NR¹⁰R¹¹, NR¹⁰(COOR¹⁰), NR¹⁰ (COOR¹¹),NR¹⁰C(O)C(O)R¹⁰, NR¹⁰C(O)C(O)R¹¹, NR¹⁰C(O)C(O)NR¹⁰R¹¹, S(O)₂R¹⁰,S(O)₂R¹¹, S(O)₂NR¹⁰R¹⁰, S(O)₂NR¹⁰R¹¹, NR¹⁰S(O)₂NR¹⁰R¹¹, NR¹⁰S(O)₂R¹⁰ orNR¹⁰S(O)₂R¹¹, provided that (1) one substituent is C(O)R¹⁰, COOR¹⁰,C(O)R¹¹, COOR¹¹, C(O)NR¹⁰R¹⁰, C(S)NR¹⁰R¹⁰, C(O)NR¹⁰R¹¹, C(S)NR¹⁰R¹¹,NR¹⁰R¹¹, NR¹⁰C(O)R¹⁰, NR¹⁰C(S)R¹⁰, NR¹⁰C(O)R¹¹, NR¹⁰C(S)R¹¹,NR¹⁰C(S)NR¹⁰R¹⁰, NR¹⁰C(S)NR¹⁰R¹¹, S(O)₂NR¹⁰R¹⁰, S(O)₂NR¹⁰R¹¹,NR¹⁰S(O)₂NR¹⁰R¹¹, NR¹⁰S(O)₂R¹⁰ or NR¹⁰S(O)₂R¹¹;

R⁴ is H, halo, haloalkyl, NO₂, CN, NR⁷R⁷, OR⁷, SR⁷, C(O)R⁷, C₁₋₁₀-alkyl,C₂₋₁₀-alkenyl, C₂₋₁₀-alkynyl or C₃₋₁₀-cycloalkyl, each of theC₁₋₁₀-alkyl, C₂₋₁₀-alkenyl, C₂₋₁₀-alkynyl and C₃₋₁₀-cycloalkyloptionally comprising 1-4 heteroatoms selected from N, O and S andoptionally substituted with 1-3 substituents of R⁹;

R⁵ is H, halo, haloalkyl, NO₂, CN, NR⁷R⁷, OR⁷; SR⁷, C(O)R⁷, C₁₋₁₀-alkyl,C₂₋₁₀-alkenyl, C₂₋₁₀-alkynyl or C₃₋₁₀-cycloalkyl, each of theC₁₋₁₀-alkyl, C₂₋₁₀-alkenyl, C₂₋₁₀-alkynyl and C₃₋₁₀-cycloalkyloptionally comprising 1-4 heteroatoms selected from N, O and S andoptionally substituted with 1-3 substituents of R⁹;

R⁷ is H, C₁₋₁₀-alkyl, C₂₋₁₀-alkenyl, C₂₋₁₀-alkynyl, C₃₋₁₀-cycloalkyl orC₄₋₁₀-cycloalkenyl, each of the C₁₋₁₀-alkyl, C₂₋₁₀-alkenyl,C₂₋₁₀-alkynyl, C₃₋₁₀-cycloalkyl and C₄₋₁₀-cycloalkenyl optionallycomprising 1-4 heteroatoms selected from N, O and S and optionallysubstituted with 1-3 substituents of NR⁸R⁹, NR⁹R⁹, OR⁸, SR⁸, OR⁹, SR⁹,C(O)R⁸, OC(O)R⁸, COOR⁸, C(O)R⁹, OC(O)R⁹, COOR⁹, C(O)NR⁸R⁹, C(O)NR⁹R⁹,NR⁹C(O)R⁸, NR⁹C(O)R⁹, NR⁹C(O)NR⁸R⁹, NR⁹C(O)NR⁹R⁹, NR⁹(COOR⁸),NR⁹(COOR⁹), OC(O)NR⁸R⁹, OC(O)NR⁹R⁹, S(O)₂R⁸, S(O)₂NR⁸R⁹, S(O)₂R⁹,S(O)₂NR⁹R⁹, NR⁹S(O)₂NR⁸R⁹, NR⁹S(O)₂NR⁹R⁹, NR⁹S(O)₂R⁸, NR⁹S(O)₂R⁹, R⁸ orR⁹;

R⁸ is a partially or fully saturated or unsaturated 5-8 memberedmonocyclic, 6-12 membered bicyclic, or 7-14 membered tricyclic ringsystem, said ring system formed of carbon atoms optionally including 1-3heteroatoms if monocyclic, 1-6 heteroatoms if bicyclic, or 1-9heteroatoms if tricyclic, said heteroatoms selected from O, N, or S, andwherein said ring system is optionally substituted independently with1-5 substituents of R⁹, oxo, NR⁹R⁹, OR⁹; SR⁹, C(O)R⁹ or a partially orfully saturated or unsaturated 5-6 membered ring of carbon atomsoptionally including 1-3 heteroatoms selected from O, N, or S, andoptionally substituted independently with 1-3 substituents of R⁹;

alternatively, R⁷ and R⁸ taken together form a saturated or partially orfully unsaturated 5-6 membered ring of carbon atoms optionally including1-3 heteroatoms selected from O, N, or S, and the ring optionallysubstituted independently with 1-3 substituents of R⁹;

R⁹ is H, halo, haloalkyl, CN, OH, NO₂, NH₂, acetyl, C₁₋₁₀-alkyl,C₂₋₁₀-alkenyl, C₂₋₁₀-alkynyl, C₃₋₁₀-cycloalkyl, C₄₋₁₀-cycloalkenyl,C₁₋₁₀-alkylamino-, C₁₋₁₀-dialkylamino-, C₁₋₁₀-alkoxyl, C₁₋₁₀-thioalkoxylor a saturated or partially or fully unsaturated 5-8 membered monocyclicor a 6-12 membered bicyclic, said ring system formed of carbon atomsoptionally including 1-3 heteroatoms if monocyclic or 1-6 heteroatoms ifbicyclic, said heteroatoms selected from O, N, or S, wherein each of theC₁₋₁₀-alkyl, C₂₋₁₀-alkenyl, C₂₋₁₀-alkynyl, C₃₋₁₀-cycloalkyl,C₄₋₁₀-cycloalkenyl, C₁₋₁₀-alkylamino-, C₁₋₁₀-dialkylamino-,C₁₋₁₀-alkoxyl, C₁₋₁₀-thioalkoxyl and ring of said ring system isoptionally substituted independently with 1-3 substituents of halo,haloalkyl, CN, NO₂, NH₂, OH, oxo, methyl, methoxyl, ethyl, ethoxyl,propyl, propoxyl, isopropyl, cyclopropyl, butyl, isobutyl, tert-butyl,methylamine, dimethylamine, ethylamine, diethylamine, propylamine,isopropylamine, dipropylamine, diisopropylamine, benzyl or phenyl;

R¹⁰ is H, halo, haloalkyl, CN, NO₂, C₁₋₁₀-alkyl, C₂₋₁₀-alkenyl,C₂₋₁₀-alkynyl, C₃₋₁₀-cycloalkyl or C₄₋₁₀-cycloalkenyl, each of theC₁₋₁₀-alkyl, C₂₋₁₀-alkenyl, C₂₋₁₀-alkynyl, C₃₋₁₀-cycloalkyl andC₄₋₁₀-cycloalkenyl optionally comprising 1-4 heteroatoms selected fromN, O and S and optionally substituted with 1-5 substituents of R¹¹, R¹²or R¹⁶, NR¹¹R¹², NR¹²R¹², OR¹¹, SR¹¹, OR¹², SR¹², C(O)R¹¹, OC(O)R¹¹,COOR¹¹, C(O)R¹², OC(O)R¹², COOR¹², C(O)NR¹¹R¹², NR¹²C(O)R¹¹,C(O)NR¹²R¹², NR¹²C(O)R¹², NR¹²C(O)NR¹¹R¹², NR¹²C(O)NR¹²R¹², NR¹²(COOR¹¹), NR¹²(COOR¹²), OC(O)NR¹¹R¹², OC(O)NR¹²R¹², S(O)₂R¹¹, S(O)₂R¹²,S(O)₂NR¹¹R¹², S(O)₂NR¹²R¹², NR¹²R¹²S(O)₂NR¹¹R¹², NR¹²S(O)₂NR¹²R¹²,NR¹²S(O)₂R¹¹, NR¹²S(O)₂R¹², NR¹²S(O)R¹¹ or NR¹²S(O)₂R¹²;

R¹¹ is a partially or fully saturated or unsaturated 5-8 memberedmonocyclic, 6-12 membered bicyclic, or 7-14 membered tricyclic ringsystem, said ring system formed of carbon atoms optionally including 1-3heteroatoms if monocyclic, 1-6 heteroatoms if bicyclic, or 1-9heteroatoms if tricyclic, said heteroatoms selected from O, N, or S, andwherein each ring of said ring system is optionally substitutedindependently with 1-5 substituents of R¹², R¹³, R¹⁴ or R¹⁶;

alternatively, R¹⁰ and R¹¹ taken together form a partially or fullysaturated or unsaturated 5-6 membered ring of carbon atoms optionallyincluding 1-3 heteroatoms selected from O, N, or S, and the ringoptionally substituted independently with 1-5 substituents of R¹², R¹³,R¹⁴ or R¹⁶;

R¹² is H, C₁₋₁₀-alkyl, C₂₋₁₀-alkenyl, C₂₋₁₀-alkynyl, C₃₋₁₀-cycloalkyl,C₄₋₁₀-cycloalkenyl, C₁₋₁₀-alkylamino-, C₁₋₁₀-dialkylamino-,C₁₋₁₀-alkoxyl or C₁₋₁₀-thioalkyl, each of which is optionallysubstituted independently with 1-5 substituents of R¹³, R¹⁴, R¹⁵ or R¹⁶;

R¹³ is NR¹⁴R¹⁵, NR¹⁵R¹⁵, OR¹⁴; SR¹⁴, OR¹⁵; SR¹⁵, C(O)R¹⁴, OC(O)R¹⁴,COOR¹⁴, C(O)R¹⁵, OC(O)R¹⁵, COOR¹⁵, C(O)NR¹⁴R¹⁵, C(O)NR¹⁵R¹⁵,NR¹⁴C(O)R¹⁴, NR¹⁵C(O)R¹⁴, NR¹⁴C(O)R¹⁵, NR¹⁵C(O)R¹⁵, NR¹⁵C(O)NR¹⁴R¹⁵,NR¹⁵C(O)NR¹⁵R¹⁵, NR¹⁵(COOR¹⁴), NR¹⁵(COOR¹⁵), OC(O)NR¹⁴R¹⁵, OC(O)NR¹⁵R¹⁵,S(O)₂R¹⁴, S(O)₂R¹⁵, S(O)₂NR¹⁴R¹⁵, S(O)₂NR¹⁵R¹⁵, NR¹⁴S(O)₂NR¹⁴R¹⁵,NR¹⁵S(O)₂NR¹⁵R¹⁵, NR¹⁴S(O)₂R¹⁴ or NR¹⁵S(O)₂R¹⁵;

R¹⁴ is a partially or fully saturated or unsaturated 5-8 membered or asaturated or partially or fully unsaturated 5-8 membered monocyclic,6-12 membered bicyclic, or 7-14 membered tricyclic ring system, saidring system formed of carbon atoms optionally including 1-3 heteroatomsif monocyclic, 1-6 heteroatoms if bicyclic, or 1-9 heteroatoms iftricyclic, said heteroatoms selected from O, N, or S, and wherein eachring of said ring system is optionally substituted independently with1-5 substituents of R¹⁵ or R¹⁶;

R¹⁵ is H or C₁₋₁₀-alkyl, C₂₋₁₀-alkenyl, C₂₋₁₀-alkynyl, C₃₋₁₀-cycloalkyl,C₄₋₁₀-cycloalkenyl, C₁₋₁₀-alkylamino-, C₁₋₁₀-dialkylamino-,C₁₋₁₀-alkoxyl or C₁₋₁₀-thioalkoxyl, each of which is optionallysubstituted independently with 1-5 substituents of R¹⁶;

R¹⁶ is H, halo, haloalkyl, CN, OH, NO₂, NH₂, OH, methyl, methoxyl,ethyl, ethoxyl, propyl, propoxyl, isopropyl, cyclopropyl, butyl,isobutyl, tert-butyl, methylamino, dimethylamino, ethylamino,diethylamino, isopropylamino, oxo, acetyl, benzyl, phenyl, cyclopropyl,cyclobutyl or a partially or fully saturated or unsaturated 5-8 memberedmonocyclic or 6-12 membered bicyclic ring system, said ring systemformed of carbon atoms optionally including 1-3 heteroatoms ifmonocyclic or 1-6 heteroatoms if bicyclic, said heteroatoms selectedfrom O, N, or S, and optionally substituted independently with 1-5substituents of halo, haloalkyl, CN, NO₂, NH₂, OH, methyl, methoxyl,ethyl, ethoxyl, propyl, propoxyl, isopropyl, cyclopropyl, butyl,isobutyl, tert-butyl, methylamino, dimethylamino, ethylamino,diethylamino, isopropylamino, benzyl or phenyl;

and provided that (1) when said at least one substituent on said R² ringsystem is C(O)NR¹⁰R¹⁰ or C(O)NR¹⁰R¹¹, then R¹⁰ and R¹¹, independently,are not —CH₂-L-Q or —C(C₁₋₆alkyl)(C₁₋₆alkyl)-L-Q, wherein L is —O—,—NH—, —NHC(O)—, —NHC(O)N—, —NHC(═NH)N— or —CO₂— and Q is H, substitutedor unsubstituted C₁₋₆alkyl, substituted or unsubstituted aryl,substituted or unsubstituted heterocyclyl, substituted or unsubstitutedheteraryl or C₁₋₆alkyl substituted with aryl, heterocyclyl orheteroaryl; (2) where the sole substituent on said R² ring system isR¹⁰, said substituent is not C₁-alkyl-C(O)NR¹¹R¹², C₁-alkyl-NR¹²C(O)R¹¹,C₁-alkyl-C(O)NR¹²R¹² or C₁-alkyl-NR¹²C(O)R¹², wherein the C₁-alkylportion is CH₂ or substituted with C₁₋₆-alkyl or cycloalky; or (3) whensaid R² is a phenyl ring substituted with C(O)NR¹⁰R¹⁰ or C(O)NR¹⁰R¹¹meta to the alkynyl group of Formula I, then either (a) R¹ is nothalogen, C₁₋₆alkyl, C₁₋₆alkoxyl or hydroxyl or (b) where R¹ and R³ takentogether with the atoms to which they are attached form a partially orfully unsaturated 5- or 6-membered ring of carbon atoms optionallyincluding 1-3 heteroatoms selected from O, N, or S, said ring is notsubstituted with halogen, C₁₋₆alkyl, C₁₋₆alkoxyl or hydroxylsubstituents.

In another embodiment, the compounds of the embodiment immediatelyabove, are generally defined by Formula I above, wherein R¹ is R⁷,NR⁷R⁷, NR⁷R⁸, SR⁷, C(O)R⁷, C(O)NR⁷R⁷, C(S)NR⁷R⁷, NR⁷C(O)R⁷, NR⁷C(S)R⁷,NR⁷C(O)NR⁷R⁷, NR⁷C(S)NR⁷R⁷, NR⁷(COOR⁷), C(O)NR⁷R⁸, C(S)NR⁷R⁸,NR⁷C(O)NR⁷R⁸, NR⁷C(S)NR⁷R⁸, S(O)₂R⁷, S(O)₂NR⁷R⁷, NR⁷S(O)₂NR⁷R⁷,NR⁷S(O)₂R⁷, S(O)₂NR⁷R⁸ or NR⁷S(O)₂NR⁷R⁸;

R² is a phenyl, naphthyl, pyridyl, pyrimidinyl, triazinyl, quinolinyl,isoquinolinyl, quinazolinyl, isoquinazolinyl, thiophenyl, furyl,pyrrolyl, imidazolyl, triazolyl, thiazolyl, oxazolyl, isoxazolyl,isothiazolyl, indolyl, isoindolyl, benzofuranyl, dihydrobenzofuranyl,benzothiophenyl or benzimidazolyl ring system, said ring systemsubstituted independently with 1-3 substituents of R¹⁰, R¹¹, R¹⁵,NR¹⁰R¹⁰, NR¹⁰R¹¹, OR¹⁰, SR¹⁰, OR¹¹, SR¹¹, C(O)R¹⁰, C(S)R¹⁰, C(NCN)R¹⁰,C(O)R¹¹, C(S)R¹¹, C(NCN)R¹¹, C(O)C(O)R¹⁰, OC(O)R¹⁰, COOR¹⁰, C(O)SR¹⁰,C(O)C(O)R¹¹, OC(O)R¹¹, COOR¹¹, C(O)SR¹¹, C(O)NR¹⁰R¹⁰, C(S)NR¹⁰R¹⁰,C(O)NR¹⁰R¹¹, C(S)NR¹⁰NR¹¹, OC(O)NR¹⁰R¹¹, NR¹⁰C(O)R¹⁰, NR¹⁰C(O)R¹¹,NR¹⁰C(S)R¹⁰, NR¹⁰C(S)R¹¹, NR¹⁰C(O)NR¹⁰R¹⁰, NR¹⁰C(O)NR¹⁰R¹¹,NR¹⁰C(S)NR¹⁰R¹⁰, NR¹⁰C(S)NR¹⁰R¹¹, NR¹⁰(COOR¹⁰), NR¹⁰(COOR¹¹),NR¹⁰C(O)C(O)R¹⁰, NR¹⁰C(O)C(O)R¹¹, NR¹⁰C(O)C(O)NR¹⁰R¹¹, S(O)₂R¹⁰,S(O)₂R¹¹, S(O)₂NR¹⁰R¹⁰, S(O)₂NR¹⁰R¹¹, NR¹⁰S(O)₂NR¹⁰R¹¹, NR¹⁰S(O)₂R¹⁰ orNR¹⁰S(O)₂R¹¹, provided that one substituent is C(O)R¹¹, COOR¹¹,C(O)NR¹⁰R¹¹, C(S)NR¹⁰R¹¹, NR¹⁰R¹¹, NR¹⁰C(O)R¹¹, NR¹⁰C(S)R¹¹,NR¹⁰C(O)NR¹⁰R¹¹, NR¹⁰C(S)NR¹⁰R¹¹, NR¹⁰(COOR¹¹), S(O)₂NR¹⁰R¹¹,NR¹⁰S(O)₂NR¹⁰R¹¹ or NR¹⁰S(O)₂R¹¹;

R⁴ is H, halo, haloalkyl, NO₂, CN, NH₂, N—C₁₋₁₀-alkyl, N—C₁₋₁₀-dialkyl,O—C₁₋₁₀-alkyl, S—C₁₋₁₀-alkyl, C₁₋₁₀-alkyl, C₂₋₁₀-alkenyl, C₂₋₁₀-alkynylor C₃₋₁₀-cycloalkyl;

R⁵ is H, halo, haloalkyl, NO₂, CN, NH₂, N—C₁₋₁₀-alkyl, N—C₁₋₁₀-dialkyl,O—C₁₋₁₀-alkyl, S—C₁₋₁₀-alkyl, C₁₋₁₀-alkyl, C₂₋₁₀-alkenyl, C₂₋₁₀-alkynylor C₃₋₁₀-cycloalkyl;

R⁷ is H, C₁₋₁₀-alkyl, C₂₋₁₀-alkenyl, C₂₋₁₀-alkynyl or C₃₋₁₀-cycloalkyl,each of the C₁₋₁₀-alkyl, C₂₋₁₀-alkenyl, C₂₋₁₀-alkynyl andC₃₋₁₀-cycloalkyl optionally comprising 1-4 heteroatoms selected from N,O and S and optionally substituted with 1-3 substituents of NR⁸R⁹,NR⁹R⁹, OR⁸, SR⁸, OR⁹, SR⁹, C(O)R⁸, OC(O)R⁸, COOR⁸, C(O)R⁹, OC(O)R⁹,COOR⁹, C(O)NR⁸R⁹, C(O)NR⁹R⁹, NR⁹C(O)R⁸, NR⁹C(O)R⁹, NR⁹C(O)NR⁸R⁹,NR⁹C(O)NR⁹R⁹, NR⁹(COOR⁸), NR⁹(COOR⁹), OC(O)NR⁸R⁹, OC(O)NR⁹R⁹, S(O)₂R⁸,S(O)₂NR⁸R⁹, S(O)₂R⁹, S(O)₂NR⁹R⁹, NR⁹S(O)₂NR⁸R⁹, NR⁹S(O)₂NR⁹R⁹,NR⁹S(O)₂R⁸, NR⁹S(O)₂R⁹, R⁸ or R⁹;

R⁸ is a ring system of phenyl, naphthyl, pyridyl, pyrimidinyl,pyrrolidinyl, piperidinyl, piperazinyl, triazinyl, quinolinyl,isoquinolinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl,quinazolinyl, isoquinazolinyl, tetrahydroquinazolinyl,tetrahydroisoquinazolinyl, morpholinyl, thiophenyl, furyl, dihydrofuryl,tetrahydrofuryl, pyrrolyl, imidazolyl, triazolyl, thiazolyl, oxazolyl,isoxazolyl, isothiazolyl, indolyl, isoindolyl, indolinyl, benzofuranyl,dihydrobenzofuranyl, benzothiophenyl or benzimidazolyl, said ring systemoptionally substituted independently with 1-3 substituents of R⁹, oxo,NR⁹R⁹, OR⁹; SR⁹, C(O)R⁹ or a partially or fully saturated or unsaturated5-6 membered ring of carbon atoms optionally including 1-3 heteroatomsselected from O, N, or S, and optionally substituted independently with1-3 substituents of R⁹;

alternatively, R⁷ and R⁸ taken together form a saturated or partially orfully unsaturated 5-6 membered ring of carbon atoms optionally including1-3 heteroatoms selected from O, N, or S, and the ring optionallysubstituted independently with 1-3 substituents of R⁹;

R⁹ is H, halo, haloalkyl, CN, OH, NO₂, NH₂, acetyl, C₁₋₁₀-alkyl,C₂₋₁₀-alkenyl, C₂₋₁₀-alkynyl, C₃₋₁₀-cycloalkyl, C₁₋₁₀-alkylamino-,C₁₋₁₀-dialkylamino-, C₁₋₁₀-alkoxyl, C₁₋₁₀-thioalkoxyl or a ring systemof phenyl, naphthyl, pyridyl, pyrimidinyl, pyrrolidinyl, piperidinyl,piperazinyl, quinolinyl, isoquinolinyl, tetrahydroquinolinyl,tetrahydroisoquinolinyl, quinazolinyl, isoquinazolinyl,tetrahydroquinazolinyl, tetrahydroisoquinazolinyl, morpholinyl,thiophenyl, furyl, dihydrofuryl, tetrahydrofuryl, pyrrolyl, imidazolyl,thiazolyl, oxazolyl, isoxazolyl, isothiazolyl, indolyl, isoindolyl,indolinyl, benzofuranyl, dihydrobenzofuranyl, benzothiophenyl andbenzimidazolyl, each of the C₁₋₁₀-alkyl, C₂₋₁₀-alkenyl, C₂₋₁₀-alkynyl,C₃₋₁₀-cycloalkyl, C₄₋₁₀-cycloalkenyl, C₁₋₁₀-alkylamino-,C₁₋₁₀-dialkylamino-, C₁₋₁₀-alkoxyl, C₁₋₁₀-thioalkoxyl and ring systemoptionally substituted independently with 1-3 substituents of halo,haloalkyl, CN, NO₂, NH₂, OH, oxo, methyl, methoxyl, ethyl, ethoxyl,propyl, propoxyl, isopropyl, cyclopropyl, butyl, isobutyl, tert-butyl,methylamine, dimethylamine, ethylamine, diethylamine, propylamine,isopropylamine, dipropylamine, diisopropylamine, benzyl or phenyl;

R¹⁰ is H, halo, haloalkyl, CN, NO₂, C₁₋₁₀-alkyl, C₂₋₁₀-alkenyl,C₂₋₁₀-alkynyl, C₃₋₁₀-cycloalkyl or C₄₋₁₀-cycloalkenyl, each of theC₁₋₁₀-alkyl, C₂₋₁₀-alkenyl, C₂₋₁₀-alkynyl, C₃₋₁₀-cycloalkyl andC₄₋₁₀-cycloalkenyl optionally comprising 1-4 heteroatoms selected fromN, O and S and optionally substituted with 1-5 substituents of R¹¹, R¹²or R¹⁶, NR¹¹R¹², NR¹²R¹², OR¹¹, SR¹¹, OR¹², SR¹², C(O)R¹¹, OC(O)R¹¹,COOR¹¹, C(O)R¹², OC(O)R¹², COOR¹², C(O)NR¹¹R¹², NR¹²C(O)R¹¹,C(O)NR¹²R¹², NR¹²C(O)R¹², NR¹²C(O)NR¹¹R¹², NR¹²C(O)NR¹²R¹²,NR¹²(COOR¹¹), NR¹²(COOR¹²), OC(O)NR¹¹R¹², OC(O)NR¹²R¹², S(O)₂R¹¹,S(O)₂R¹², S(O)₂NR¹¹R¹², S(O)²NR¹²R¹², NR¹²S(O)₂NR¹¹R¹²,NR¹²S(O)₂NR¹²R¹², NR¹²S(O)₂R¹¹, NR¹²S(O)₂R¹², NR¹²S(O)₂R¹¹ orNR¹²S(O)₂R¹²;

R¹¹ is a ring system of phenyl, naphthyl, pyridyl, pyrimidinyl,triazinyl, quinolinyl, isoquinolinyl, tetrahydroquinolinyl,tetrahydroisoquinolinyl, quinazolinyl, isoquinazolinyl,tetrahydroquinazolinyl, tetrahydroisoquinazolinyl, morpholinyl,thiophenyl, furyl, dihydrofuryl, tetrahydrofuryl, pyrrolyl, imidazolyl,triazolyl, thiazolyl, oxazolyl, isoxazolyl, isothiazolyl, indolyl,isoindolyl, indolinyl, benzofuranyl, dihydrobenzofuranyl,benzothiophenyl or benzimidazolyl, said ring system optionallysubstituted independently with 1-5 substituents of R¹², R¹³, R¹⁴ or R¹⁶;

alternatively, R¹⁰ and R¹¹ taken together form a partially or fullysaturated or unsaturated 5-6 membered ring of carbon atoms optionallyincluding 1-3 heteroatoms selected from O, N, or S, and the ringoptionally substituted independently with 1-5 substituents of R¹², R¹³,R¹⁴ or R¹⁶;

R¹² is H, C₁₋₁₀-alkyl, C₂₋₁₀-alkenyl, C₂₋₁₀-alkynyl, C₃₋₁₀-cycloalkyl,C₄₋₁₀-cycloalkenyl, C₁₋₁₀-alkylamino-, C₁₋₁₀-dialkylamino-,C₁₋₁₀-alkoxyl or C₁₋₁₀-thioalkyl, each of which is optionallysubstituted independently with 1-5 substituents of R¹³, R¹⁴, R¹⁵ or R¹⁶;

R¹³ is NR¹⁴R¹⁵, NR¹⁵R¹⁵, OR¹⁴; SR¹⁴, OR¹⁵; SR¹⁵, C(O)R¹⁴, OC(O)R¹⁴,COOR¹⁴, C(O)R¹⁵, OC(O)R¹⁵, COOR¹⁵, C(O)NR¹⁴R¹⁵, C(O)NR¹⁵R¹⁵,NR¹⁴C(O)R¹⁴, NR¹⁵C(O)R¹⁴, NR¹⁴C(O)R¹⁵, NR¹⁵C(O)R¹⁵, NR¹⁵C(O)NR¹⁴R¹⁵,NR¹⁵C(O)NR¹⁵R¹⁵, NR¹⁵(COOR¹⁴), NR¹⁵(COOR¹⁵), OC(O)NR¹⁴R¹⁵, OC(O)NR¹⁵R¹⁵,S(O)₂R¹⁴, S(O)₂R¹⁵, S(O)₂NR¹⁴R¹⁵, S(O)₂NR¹⁵R¹⁵, NR¹⁴S(O)₂NR¹⁴R¹⁵,NR¹⁵S(O)₂NR¹⁵R¹⁵, NR¹⁴S(O)₂R¹⁴ or NR¹⁵S(O)₂R¹⁵;

R¹⁴ is a partially or fully saturated or unsaturated 5-8 membered or asaturated or partially or fully unsaturated 5-8 membered monocyclic,6-12 membered bicyclic, or 7-14 membered tricyclic ring system, saidring system formed of carbon atoms optionally including 1-3 heteroatomsif monocyclic, 1-6 heteroatoms if bicyclic, or 1-9 heteroatoms iftricyclic, said heteroatoms selected from O, N, or S, and wherein eachring of said ring system is optionally substituted independently with1-5 substituents of R¹⁵ or R¹⁶;

R¹⁵ is H or C₁₋₁₀-alkyl, C₂₋₁₀-alkenyl, C₂₋₁₀-alkynyl, C₃₋₁₀-cycloalkyl,C₄₋₁₀-cycloalkenyl, C₁₋₁₀-alkylamino-, C₁₋₁₀-dialkylamino-,C₁₋₁₀-alkoxyl or C₁₋₁₀-thioalkoxyl, each of which is optionallysubstituted independently with 1-5 substituents of R¹⁶; and

R¹⁶ is H, halo, haloalkyl, CN, OH, NO₂, NH₂, OH, methyl, methoxyl,ethyl, ethoxyl, propyl, propoxyl, isopropyl, cyclopropyl, butyl,isobutyl, tert-butyl, methylamino, dimethylamino, ethylamino,diethylamino, isopropylamino, oxo, acetyl, benzyl, phenyl, cyclopropyl,cyclobutyl or a partially or fully saturated or unsaturated 5-8 memberedmonocyclic or 6-12 membered bicyclic ring system, said ring systemformed of carbon atoms optionally including 1-3 heteroatoms ifmonocyclic or 1-6 heteroatoms if bicyclic, said heteroatoms selectedfrom O, N, or S, and optionally substituted independently with 1-5substituents of halo, haloalkyl, CN, NO₂, NH₂, OH, methyl, methoxyl,ethyl, ethoxyl, propyl, propoxyl, isopropyl, cyclopropyl, butyl,isobutyl, tert-butyl, methylamino, dimethylamino, ethylamino,diethylamino, isopropylamino, benzyl or phenyl.

In another embodiment, the compounds of the embodiment immediatelyabove, are generally defined by Formula I above, wherein R¹ is NH₂ orNCH₃, in conjunction with any of the above or below embodiments.

In another embodiment, the compounds are generally defined by Formula Iabove, wherein

A² is CH;

A³ is CH;

R¹ is NR⁷R⁷, NR⁷R⁸, SR⁷, C(O)R⁷, COOR⁷, C(O)NR⁷R⁷, NR⁷C(O)R⁷,NR⁷C(O)NR⁷R⁷, NR⁷(COOR⁷), C(O)NR⁷R⁸, NR⁷C(O)R⁸, NR⁷C(O)NR⁷R⁸,NR⁷(COOR⁸), S(O)₂R⁷, S(O)₂NR⁷R⁷, NR⁷S(O)₂NR⁷R⁷, NR⁷S(O)₂R⁷, S(O)₂NR⁷R⁸,NR⁷S(O)₂NR⁷R⁸ or NR⁷S(O)₂R⁸;

R² is a phenyl, naphthyl, pyridyl, pyrimidinyl, triazinyl, quinolinyl,isoquinolinyl, quinazolinyl, isoquinazolinyl, thiophenyl, furyl,pyrrolyl, imidazolyl, triazolyl, thiazolyl, oxazolyl, isoxazolyl,isothiazolyl, indolyl, isoindolyl, benzofuranyl, dihydrobenzofuranyl,benzothiophenyl or benzimidazolyl ring system, said ring systemsubstituted independently with 1-3 substituents of R¹⁰, R¹¹, R¹⁵,NR¹⁰R¹⁰, NR¹⁰R¹¹, OR¹⁰, SR¹⁰, OR¹¹, SR¹¹, C(O)R¹⁰, C(S)R¹⁰, C(NCN)R¹⁰,C(O)R¹¹R¹¹, C(S)R¹¹, C(NCN)R¹¹, C(O)C(O)R¹⁰, OC(O)R¹⁰, COOR¹⁰, C(O)SR¹⁰,C(O)C(O)R¹¹, OC(O)R¹¹, COOR¹¹, C(O)SR¹¹, C(O)NR¹⁰R¹⁰, C(S)NR¹⁰R¹⁰,C(O)NR¹⁰R¹¹, C(S)NR¹⁰R¹¹, OC(O)NR¹⁰R¹¹, NR¹⁰C(O)R¹⁰, NR¹⁰C(O)R¹¹,NR¹⁰C(S)R¹⁰, NR¹⁰C(S)R¹¹, NR¹⁰C(O)NR¹⁰R¹⁰, NR¹⁰C(O)NR¹⁰R¹¹,NR¹⁰C(S)NR¹⁰R¹⁰, NR¹⁰C(S)NR¹⁰R¹¹, NR¹⁰(COOR¹⁰), NR¹⁰(COOR¹¹),NR¹⁰C(O)C(O)R¹⁰, NR¹⁰C(O)C(O)R¹¹, NR¹⁰C(O)C(O)NR¹⁰R¹¹, S(O)₂R¹⁰,S(O)₂R¹¹, S(O)₂NR¹⁰R¹⁰, S(O)₂NR¹⁰R¹¹, NR¹⁰S(O)₂NR¹⁰R¹¹, NR¹⁰S(O)₂R¹⁰ orNR¹⁰S(O)₂R¹¹, provided that one substituent is C(O)NR¹⁰R¹⁰, C(S)NR¹⁰R¹⁰,C(O)NR¹⁰R¹¹, C(S)NR¹⁰R¹¹, NR¹⁰R¹¹, NR¹⁰C(O)R¹⁰, NR¹⁰C(S)R¹⁰,NR¹⁰C(O)R¹¹, NR¹⁰C(S)R¹¹, NR¹⁰C(S)NR¹⁰R¹⁰, NR¹⁰C(S)NR¹⁰R¹¹,S(O)₂NR¹⁰R¹⁰, S(O)₂NR¹⁰R¹¹, NR¹⁰S(O)₂NR¹⁰R¹¹, NR¹⁰S(O)₂R¹⁰ orNR¹⁰S(O)₂R¹¹;

R⁷ is H, C₁₋₁₀-alkyl or C₃₋₁₀-cycloalkyl, each of the C₁₋₁₀-alkyl andC₃₋₁₀-cycloalkyl optionally comprising 1-2 heteroatoms selected from N,O and S and optionally substituted with 1-3 substituents of R⁹;

R⁸ is a phenyl, naphthyl, pyridyl, pyrimidinyl, pyrrolidinyl,piperidinyl, piperazinyl, quinolinyl, isoquinolinyl,tetrahydroquinolinyl, tetrahydroisoquinolinyl, quinazolinyl,isoquinazolinyl, tetrahydroquinazolinyl, tetrahydroisoquinazolinyl,morpholinyl, thiophenyl, furyl, dihydrofuryl, tetrahydrofuryl, pyrrolyl,imidazolyl, thiazolyl, oxazolyl, isoxazolyl, isothiazolyl, indolyl,isoindolyl, indolinyl, benzofuranyl, dihydrobenzofuranyl,benzothiophenyl or benzimidazolyl ring system, said ring systemoptionally substituted independently with 1-3 substituents of R⁹, oxo,NR⁹R⁹, OR⁹; SR⁹, C(O)R⁹ or a partially or fully saturated or unsaturated5-6 membered ring of carbon atoms optionally including 1-3 heteroatomsselected from O, N, or S, and optionally substituted independently with1-3 substituents of R⁹;

alternatively, R⁷ and R⁸ taken together form a 5-6 membered ringselected from pyrrolidine, piperidine, morpholine and piperazine, thering optionally substituted independently with 1-3 substituents of R⁹;

R⁹ is H, halo, haloalkyl, CN, OH, NO₂, NH₂, acetyl, C₁₋₁₀-alkyl,C₂₋₁₀-alkenyl, C₂₋₁₀-alkynyl, C₃₋₁₀-cycloalkyl, C₁₋₁₀-alkylamino-,C₁₋₁₀-dialkylamino-, C₁₋₁₀-alkoxyl, C₁₋₁₀-thioalkoxyl or a ring systemof phenyl, naphthyl, pyridyl, pyrimidinyl, pyrrolidinyl, piperidinyl,piperazinyl, quinolinyl, isoquinolinyl, tetrahydroquinolinyl,tetrahydroisoquinolinyl, quinazolinyl, isoquinazolinyl,tetrahydroquinazolinyl, tetrahydroisoquinazolinyl, morpholinyl,thiophenyl, furyl, dihydrofuryl, tetrahydrofuryl, pyrrolyl, imidazolyl,thiazolyl, oxazolyl, isoxazolyl, isothiazolyl, indolyl, isoindolyl,indolinyl, benzofuranyl, dihydrobenzofuranyl, benzothiophenyl andbenzimidazolyl, wherein each of the C₁₋₁₀-alkyl, C₂₋₁₀-alkenyl,C₂₋₁₀-alkynyl, C₃₋₁₀-cycloalkyl, C₄₋₁₀-cycloalkenyl, C₁₋₁₀-alkylamino-,C₁₋₁₀-dialkylamino-, C₁₋₁₀-alkoxyl, C₁₋₁₀-thioalkoxyl and ring system isoptionally substituted independently with 1-3 substituents of halo,haloalkyl, CN, NO₂, NH₂, OH, oxo, methyl, methoxyl, ethyl, ethoxyl,propyl, propoxyl, isopropyl, cyclopropyl, butyl, isobutyl, tert-butyl,methylamine, dimethylamine, ethylamine, diethylamine, propylamine,isopropylamine, dipropylamine, diisopropylamine, benzyl or phenyl;

R¹⁰ is H, C₁₋₁₀-alkyl, C₂₋₁₀-alkenyl, C₂₋₁₀-alkynyl or C₃₋₁₀-cycloalkyl,each of the C₁₋₁₀-alkyl, C₂₋₁₀-alkenyl, C₂₋₁₀-alkynyl andC₃₋₁₀-cycloalkyl optionally comprising 1-4 heteroatoms selected from N,O and S and optionally substituted with 1-3 substituents of R¹¹, R¹² orR¹⁶, NR¹¹R¹², NR¹²R¹², OR¹¹, SR¹¹, OR¹², SR¹², C(O)R¹¹, OC(O)R¹¹,COOR¹¹, C(O)R¹², OC(O)R¹², COOR¹², C(O)NR¹¹R¹², NR¹²C(O)R¹¹,C(O)NR¹²R¹², NR¹²C(O)R¹², NR¹²C(O)NR¹¹R¹², NR¹²C(O)NR¹²R¹²,NR¹²(COOR¹¹), NR¹²(COOR¹²), OC(O)NR¹¹R¹², OC(O)NR¹²R¹², S(O)₂R¹¹,S(O)₂R¹², S(O)₂NR¹¹R¹², S(O)₂NR¹²R¹², NR¹²S(O)₂NR¹¹R¹², NR¹²S(O)₂NR¹²;NR¹²S(O)₂R¹¹, NR¹²S(O)₂R¹², NR¹²S(O)₂R¹¹ or NR¹²S(O)₂R¹²;

R¹¹ is a phenyl, naphthyl, pyridyl, pyrimidinyl, quinolinyl,isoquinolinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl,quinazolinyl, isoquinazolinyl, tetrahydroquinazolinyl,tetrahydroisoquinazolinyl, thiophenyl, furyl, pyrrolyl, imidazolyl,thiazolyl, oxazolyl, isoxazolyl, isothiazolyl, indolyl, isoindolyl,indolinyl, benzofuranyl, dihydrobenzofuranyl, benzothiophenyl orbenzimidazolyl ring system, said ring system optionally substitutedindependently with 1-3 substituents of R¹², R¹³, R¹⁴ or R¹⁶;

alternatively, R¹⁰ and R¹¹ taken together form a partially or fullysaturated or unsaturated 5-6 membered ring of carbon atoms optionallyincluding 1-3 heteroatoms selected from O, N, or S, said ring optionallysubstituted independently with 1-3 substituents of R¹², R¹³, R¹⁴ or R¹⁶;

R¹² is H, C₁₋₁₀-alkyl, C₂₋₁₀-alkenyl, C₂₋₁₀-alkynyl, C₃₋₁₀-cycloalkyl,C₄₋₁₀-cycloalkenyl, C₁₋₁₀-alkylamino-, C₁₋₁₀-dialkylamino-,C₁₋₁₀-alkoxyl or C₁₋₁₀-thioalkyl, each of which is optionallysubstituted independently with 1-3 substituents of R³¹, R¹⁴, R¹⁵ or R¹⁶;

R¹³ is NR¹⁴R¹⁵, NR¹⁵R¹⁵, OR¹⁴; SR¹⁴, OR¹⁵; SR¹⁵, C(O)R¹⁴, OC(O)R¹⁴,COOR¹⁴, C(O)R¹⁵, OC(O)R¹⁵, COOR¹⁵, C(O)NR¹⁴R¹⁵, C(O)NR¹⁵R¹⁵,NR¹⁴C(O)R¹⁴, NR¹⁵C(O)R¹⁴, NR¹⁴C(O)R¹⁵, NR¹⁵C(O)R¹⁵, NR¹⁵C(O)NR¹⁴R¹⁵,NR¹⁵C(O)NR¹⁵R¹⁵, NR¹⁵(COOR¹⁴), NR¹⁵(COOR¹⁵), OC(O)NR¹⁴R¹⁵, OC(O)NR¹⁵R¹⁵,S(O)₂R¹⁴, S(O)₂R¹⁵, S(O)₂NR¹⁴R¹⁵, S(O)₂NR¹⁵R¹⁵, NR¹⁴S(O)₂NR¹⁴R¹⁵,NR¹⁵S(O)₂NR¹⁵R¹⁵, NR¹⁴S(O)₂R¹⁴ or NR¹⁵S(O)₂R¹⁵;

R¹⁴ is phenyl, naphthyl, pyridyl, pyrimidinyl, pyrrolidinyl,piperidinyl, piperazinyl, quinolinyl, isoquinolinyl,tetrahydroquinolinyl, tetrahydroisoquinolinyl, quinazolinyl,isoquinazolinyl, tetrahydroquinazolinyl, tetrahydroisoquinazolinyl,morpholinyl, thiophenyl, furyl, dihydrofuryl, tetrahydrofuryl, pyrrolyl,imidazolyl, thiazolyl, oxazolyl, isoxazolyl, isothiazolyl, indolyl,isoindolyl, indolinyl, benzofuranyl, dihydrobenzofuranyl, benzoxazinyl,benzodioxazinyl, benzothiophenyl and benzimidazolyl, each of which isoptionally substituted independently with 1-5 substituents of R¹⁵ orR¹⁶;

R¹⁵ is H or C₁₋₁₀-alkyl, C₂₋₁₀-alkenyl, C₂₋₁₀-alkynyl, C₃₋₁₀-cycloalkyl,C₄₋₁₀-cycloalkenyl, C₁₋₁₀-alkylamino-, C₁₋₁₀-dialkylamino-,C₁₋₁₀-alkoxyl or C₁₋₁₀-thioalkoxyl, each of which is optionallysubstituted independently with 1-5 substituents of R¹⁶; and

R¹⁶ is H, halo, haloalkyl, CN, OH, NO₂, NH₂, OH, methyl, methoxyl,ethyl, ethoxyl, propyl, propoxyl, isopropyl, cyclopropyl, butyl,isobutyl, tert-butyl, methylamino, dimethylamino, ethylamino,diethylamino, isopropylamino, oxo, acetyl, benzyl, phenyl, cyclopropyl,cyclobutyl or a partially or fully saturated or unsaturated 5-8 memberedmonocyclic or 6-12 membered bicyclic ring system, said ring systemformed of carbon atoms optionally including 1-3 heteroatoms ifmonocyclic or 1-6 heteroatoms if bicyclic, said heteroatoms selectedfrom O, N, or S, and optionally substituted independently with 1-5substituents of halo, haloalkyl, CN, NO₂, NH₂, OH, methyl, methoxyl,ethyl, ethoxyl, propyl, propoxyl, isopropyl, cyclopropyl, butyl,isobutyl, tert-butyl, methylamino, dimethylamino, ethylamino,diethylamino, isopropylamino, benzyl or phenyl.

In yet another embodiment, the compounds are generally defined byFormula II

wherein

R² is

wherein

-   -   one of A⁶ and A⁷ is CR^(3a) and the other of A⁶ and A⁷ is        CR^(3b) or N;    -   each of A⁵, A⁸, A⁹, A¹⁰ and A¹¹ is, independently, CR^(3b) or N;    -   X² is CR^(3a);    -   each of X¹, X³ and X⁴ is, independently, CR^(3b) or N;    -   Y¹ is CR^(3b)R^(3c), NR^(3c), O or S;    -   Y² is CR^(3a)R^(3b) or NR^(3a); and    -   Z is CH or N;    -   R^(3a) is OC(O)R¹⁰, COOR¹⁰, OC(O)R¹¹, COOR¹¹, C(O)SR¹⁰,        C(O)SR¹¹, C(O)NR¹⁰R¹⁰, C(S)NR¹⁰R¹⁰, C(O)NR¹⁰R¹¹, C(S)NR¹⁰R¹¹,        NR¹⁰R¹¹, NR¹⁰C(O)R¹⁰, NR¹⁰C(S)R¹⁰, NR¹⁰C(O)R¹¹, NR¹⁰C(S)R¹¹,        NR¹⁰C(S)NR¹⁰R¹⁰, NR¹⁰C(S)NR¹⁰R¹¹, OC(O)NR¹⁰R¹¹, S(O)₂R¹¹,        S(O)₂NR¹⁰R¹⁰, S(O)₂NR¹⁰R¹¹, NR¹⁰S(O)₂NR¹⁰R¹¹, NR¹⁰S(O)₂R¹⁰ or        NR¹⁰S(O)₂R¹¹;    -   R^(3b) is H, halo, haloalkyl, CN, NO₂, NH₂, C₁₋₁₀-alkyl,        C₂₋₁₀-alkenyl, C₂₋₁₀-alkynyl or C₃₋₁₀-cycloalkyl; and    -   R^(3c) is H, CN or C₁₋₁₀-alkyl;    -   R⁴ is H, halo, haloalkyl, NO₂, CN, OH, O—C₁₋₁₀-alkyl, NH₂,        C₁₋₁₀-alkyl, C₂₋₁₀-alkenyl, C₂₋₁₀-alkynyl or C₃₋₁₀-cycloalkyl;

R⁵ is H, halo, haloalkyl, NO₂, CN, OH, NH₂, O—C₁₋₁₀-alkyl, C₁₋₁₀-alkyl,C₂₋₁₀-alkenyl, C₂₋₁₀-alkynyl or C₃₋₁₀-cycloalkyl;

Each R⁷, independently, is H, R⁸, C₁₋₁₀-alkyl, C₂₋₁₀-alkenyl orC₂₋₁₀-alkynyl, each of which is optionally substituted with 1-3substituents of NR⁸R⁹, NR⁹R⁹, OR⁸, SR⁸, OR⁹, SR⁹, C(O)R⁸, C(O)R⁹,C(O)NR⁸R⁹, C(O)NR⁹R⁹, S(O)₂R⁸, S(O)₂NR⁸R⁹, S(O)₂R⁹, S(O)₂NR⁹R⁹, R⁸ orR⁹;

alternatively, NR⁷R⁷ form a 5-6 membered heterocyclic ring selected frompyrrolidine, piperidine, morpholine and piperazine, the ring optionallysubstituted independently with 1-3 substituents of R⁹;

R⁸ is a ring system selected from phenyl, naphthyl, pyridyl,piperazinyl, triazinyl, thiophenyl, furyl, pyrrolyl, imidazolyl,triazolyl, thiazolyl, oxazolyl, isoxazolyl, isothiazolyl, indolyl,isoindolyl, benzofuranyl, benzothiophenyl, benzimidazolyl,tetrahydrofuranyl, pyrrolidinyl, oxazolinyl, isoxazolinyl, thiazolinyl,pyrazolinyl, morpholinyl, piperidinyl, pyranyl, dioxozinyl, cyclopropyl,cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl, said ring systemoptionally substituted independently with 1-3 substituents of R⁹, oxo,NR⁹R⁹, OR⁹; SR⁹, C(O)R⁹, phenyl, pyridyl, piperidyl, piperazinyl,morpholinyl or pyrrolidinyl;

R⁹ is H, halo, haloalkyl, CN, OH, NO₂, NH₂, acetyl, C₁₋₁₀-alkyl,C₂₋₁₀-alkenyl, C₂₋₁₀-alkynyl, C₃₋₁₀-cycloalkyl, C₄₋₁₀-cycloalkenyl,C₁₋₁₀-alkylamino-, C₁₋₁₀-dialkylamino-, C₁₋₁₀-alkoxyl, C₁₋₁₀-thioalkoxylor a ring system selected from phenyl, naphthyl, pyridyl, piperazinyl,triazinyl, quinolinyl, isoquinolinyl, quinazolinyl, isoquinazolinyl,thiophenyl, furyl, pyrrolyl, imidazolyl, triazolyl, thiazolyl, oxazolyl,isoxazolyl, isothiazolyl, indolyl, isoindolyl, benzofuranyl,benzothiophenyl, benzimidazolyl, tetrahydrofuranyl, pyrrolidinyl,oxazolinyl, isoxazolinyl, thiazolinyl, pyrazolinyl, morpholinyl,piperidinyl, piperazinyl, pyranyl, dioxozinyl, cyclopropyl, cyclobutyl,cyclopentyl, cyclohexyl and cycloheptyl, each of the C₁₋₁₀-alkyl,C₂₋₁₀-alkenyl, C₂₋₁₀-alkynyl, C₃₋₁₀-cycloalkyl, C₄₋₁₀-cycloalkenyl,C₁₋₁₀-alkylamino-, C₁₋₁₀-dialkylamino-, C₁₋₁₀-alkoxyl, C₁₋₁₀-thioalkoxyland ring system optionally substituted independently with 1-3substituents of halo, haloalkyl, CN, NO₂, NH₂, OH, oxo, methyl,methoxyl, ethyl, ethoxyl, propyl, propoxyl, isopropyl, cyclopropyl,butyl, isobutyl, tert-butyl, methylamino, dimethylamino, ethylamino,diethylamino, propylamine, isopropylamine, dipropylamine,diisopropylamine, benzyl or phenyl;

R¹⁰ is H, halo, haloalkyl, CN, NO₂, C₁₋₁₀-alkyl, C₂₋₁₀-alkenyl,C₂₋₁₀-alkynyl, C₃₋₁₀-cycloalkyl or C₄₋₁₀-cycloalkenyl, each of theC₁₋₁₀-alkyl, C₂₋₁₀-alkenyl, C₂₋₁₀-alkynyl, C₃₋₁₀-cycloalkyl andC₄₋₁₀-cycloalkenyl optionally comprising 1-4 heteroatoms selected fromN, O and S and optionally substituted with one or more substituents ofR¹¹, R¹² or R¹⁶, NR¹¹R¹², NR¹²R¹², OR¹¹, SR¹¹, OR¹², SR¹², C(O)R¹¹,OC(O)R¹¹, COOR¹¹, C(O)R¹², OC(O)R¹², COOR¹², C(O)NR¹¹R¹², NR¹²C(O)R¹¹,C(O)NR¹²R¹², NR¹²C(O)R¹², NR¹²C(O)NR¹¹R¹², NR¹²C(O)NR¹²R¹²,NR¹²(COOR¹¹), NR¹²(COOR¹²), OC(O)NR¹¹R¹², OC(O)NR¹²R¹², S(O)₂R¹¹,S(O)₂R¹², S(O)₂NR¹¹R¹², S(O)₂NR¹²R¹², NR¹²S(O)₂NR¹¹R¹²,NR¹²S(O)₂NR¹²R¹², NR¹²S(O)₂R¹¹, NR¹²S(O)₂R¹², NR¹²S(O)₂R¹¹ orNR¹²S(O)₂R¹²;

R¹¹ is a phenyl, naphthyl, 5,6,7,8-tetrahydronaphthyl, dihydro-indenyl,pyridyl, pyrimidinyl, triazinyl, quinolinyl, tetrahydroquinolinyl,oxo-tetrahydroquinolinyl, isoquinolinyl, oxo-tetrahydroisoquinolinyl,tetrahydroisoquinolinyl, quinazolinyl, isoquinazolinyl, thiophenyl,furyl, tetrahydrofuranyl, pyrrolyl, pyrazolyl, thieno-pyrazolyl,tetrahydropentapyrazolyl, imidazolyl, triazolyl, tetrazolyl, thiazolyl,thiadiazolyl, benzothiazolyl, oxazolyl, oxadiazolyl, benzoxazolyl,benzoxadiazolyl, isoxazolyl, isothiazolyl, indolyl, azaindolyl,2,3-dihydroindolyl, isoindolyl, indazolyl, benzofuranyl,benzothiophenyl, benzimidazolyl, imidazopyridinyl, purinyl,benzotriazolyl, oxazolinyl, isoxazolinyl, thiazolinyl, pyrrolidinyl,pyrazolinyl, morpholinyl, piperidinyl, piperazinyl, pyranyl, dioxozinyl,2,3-dihydro-1,4-benzoxazinyl, 1,3-benzodioxolyl, cyclopropyl,cyclobutyl, azetidinyl, cyclopentyl, cyclohexyl or cycloheptyl ringsystem, said ring system optionally substituted independently with 1-3substituents of R¹², R¹³, R¹⁴ or R¹⁶;

alternatively, R¹⁰ and R¹¹ taken together form a partially or fullysaturated or unsaturated 5-6 membered ring of carbon atoms optionallyincluding 1-3 heteroatoms selected from O, N, or S, and the ringoptionally substituted independently with 1-3 substituents of R¹², R¹³,R¹⁴ or R¹⁶;

R¹² is H, C₁₋₁₀-alkyl, C₂₋₁₀-alkenyl, C₂₋₁₀-alkynyl, C₃₋₁₀-cycloalkyl,C₄₋₁₀-cycloalkenyl, C₁₋₁₀-alkylamino-, C₁₋₁₀-dialkylamino-,C₁₋₁₀-alkoxyl or C₁₋₁₀-thioalkyl, each of which is optionallysubstituted independently with 1-3 substituents of R¹³, R¹⁴, R¹⁵ or R¹⁶;

R¹³ is NR¹⁴R¹⁵, NR¹⁵R¹⁵, OR¹⁴; SR¹⁴, OR¹⁵; SR¹⁵, C(O)R¹⁴, OC(O)R¹⁴,COOR¹⁴, C(O)R¹⁵, OC(O)R¹⁵, COOR¹⁵, C(O)NR¹⁴R¹⁵, C(O)NR¹⁵R¹⁵,NR¹⁴C(O)R¹⁴, NR¹⁵C(O)R¹⁴, NR¹⁴C(O)R¹⁵, NR¹⁵C(O)R¹⁵, NR¹⁵C(O)NR¹⁴R¹⁵,NR¹⁵C(O)NR¹⁵R¹⁵, NR¹⁵(COOR¹⁴), NR¹⁵(COOR¹⁵), OC(O)NR¹⁴R¹⁵, OC(O)NR¹⁵R¹⁵,S(O)₂R¹⁴, S(O)₂R¹⁵, S(O)₂NR¹⁴R¹⁵, S(O)₂NR¹⁵R¹⁵, NR¹⁴S(O)₂NR¹⁴R¹⁵,NR¹⁵S(O)₂NR¹⁵R¹⁵, NR¹⁴S(O)₂R¹⁴ or NR¹⁵S(O)₂R¹⁵;

R¹⁴ is phenyl, pyridyl, pyrimidinyl, thiophenyl, furyl, tetrahydrofuryl,pyrrolyl, pyrazolyl, thieno-pyrazolyl, imidazolyl, triazolyl, thiazolyl,thiadiazolyl, benzothiazolyl, oxazolyl, oxadiazolyl, benzoxazolyl,benzoxadiazolyl, isoxazolyl, isothiazolyl, indolyl, azaindolyl,isoindolyl, indazolyl, benzofuranyl, benzothiophenyl, benzimidazolyl,pyrrolidinyl, pyrazolinyl, morpholinyl, piperidinyl, piperazinyl,2,3-dihydro-1,4-benzoxazinyl, 1,3-benzodioxolyl, cyclopropyl,cyclobutyl, azetidinyl, cyclopentyl and cyclohexyl, each of which isoptionally substituted independently with 1-3 substituents of R¹⁵ is orR¹⁶;

R¹⁵ is H or C₁₋₁₀-alkyl, C₂₋₁₀-alkenyl, C₂₋₁₀-alkynyl, C₃₋₁₀-cycloalkyl,C₄₋₁₀-cycloalkenyl, C₁₋₁₀-alkylamino-, C₁₋₁₀-dialkylamino-,C₁₋₁₀-alkoxyl or C₁₋₁₀-thioalkoxyl, each of which is optionallysubstituted independently with 1-3 substituents of R¹⁶; and

R¹⁶ is H, halo, haloalkyl, CN, OH, NO₂, NH₂, OH, methyl, methoxyl,ethyl, ethoxyl, propyl, propoxyl, isopropyl, cyclopropyl, butyl,isobutyl, tert-butyl, methylamino, dimethylamino, ethylamino,diethylamino, isopropylamino, oxo, acetyl, benzyl, phenyl, cyclopropyl,cyclobutyl or a partially or fully saturated or unsaturated 5-8 memberedmonocyclic or 6-12 membered bicyclic ring system, said ring systemformed of carbon atoms optionally including 1-3 heteroatoms ifmonocyclic or 1-6 heteroatoms if bicyclic, said heteroatoms selectedfrom O, N, or S, and optionally substituted independently with 1-5substituents of halo, haloalkyl, CN, NO₂, NH₂, OH, methyl, methoxyl,ethyl, ethoxyl, propyl, propoxyl, isopropyl, cyclopropyl, butyl,isobutyl, tert-butyl, methylamino, dimethylamino, ethylamino,diethylamino, isopropylamino, benzyl or phenyl.

In another embodiment, the compounds are defined by Formula II above,wherein:

R² is

wherein

-   -   each of A⁵, A⁶, and A⁷ is, independently, CR^(3b) or N;    -   A⁸ is CR^(3c) or N; and    -   A⁹ is CR^(3d) or N;    -   Y¹ is O or S;    -   Y² is NR^(3a);    -   R^(3a) is COOR¹⁰, COOR¹¹, C(O)SR¹⁰, C(O)SR¹¹, C(O)NR¹⁰R¹⁰,        C(S)NR¹⁰R¹⁰, C(O)NR¹⁰R¹¹, C(S)NR¹⁰R¹¹, NR¹⁰R¹¹, NR¹⁰C(O)R¹⁰,        NR¹⁰C(S)R¹⁰, NR¹⁰C(O)R¹¹, NR¹⁰C(S)R¹¹, NR¹⁰C(S)NR¹⁰R¹⁰,        NR¹⁰C(S)NR¹⁰R¹¹, S(O)₂NR¹⁰R¹⁰, S(O)₂NR¹⁰R¹¹, NR¹⁰S(O)₂NR¹⁰R¹¹,        NR¹⁰S(O)₂R¹⁰ or NR¹⁰S(O)₂R¹¹;    -   R^(3b) is H, halo, haloalkyl, CN, NO₂, NH₂, C₁₋₁₀-alkyl,        C₂₋₁₀-alkenyl, C₂₋₁₀-alkynyl or C₃₋₁₀-cycloalkyl; R^(3c) is H,        halo, haloalkyl, CN, NO₂, NH₂, C₁₋₁₀-alkyl, C₂₋₁₀-alkenyl,        C₂₋₁₀-alkynyl or C₃₋₁₀-cycloalkyl;    -   R^(3c) is H, halo, haloalkyl, CN, NO₂, NH₂, C₁₋₁₀-alkyl,        C₂₋₁₀-alkenyl, C₂₋₁₀-alkynyl or C₃₋₁₀-cycloalkyl;    -   R^(3d) is H, halo, haloalkyl, CN, NO₂, NH₂, C₁₋₁₀-alkyl,        C₂₋₁₀-alkenyl, C₂₋₁₀-alkynyl or C₃₋₁₀-cycloalkyl; and    -   alternatively, R^(3c) and R^(3d) taken together with the atoms        to which they are attached form a phenyl or tetrahydrofuranyl        ring system, optionally substituted with 1-3 substituents of        halo, haloalkyl, CN, NO₂, NH₂, C₁₋₁₀-alkyl, C₂₋₁₀-alkenyl,        C₂₋₁₀-alkynyl or C₃₋₁₀-cycloalkyl;

R⁴ is H, C₁₋₁₀-alkyl or O—C₁₋₁₀-alkyl;

R⁵ is H, C₁₋₁₀-alkyl or O—C₁₋₁₀-alkyl;

R⁷ is H or C₁₋₁₀-alkyl;

R⁸ is H or C₁₋₁₀-alkyl;

R¹⁰ is H, halo, haloalkyl, CN, NO₂, C₁₋₁₀-alkyl, C₂₋₁₀-alkenyl,C₂₋₁₀-alkynyl, C₃₋₁₀-cycloalkyl or C₄₋₁₀-cycloalkenyl, each of theC₁₋₁₀-alkyl, C₂₋₁₀-alkenyl, C₂₋₁₀-alkynyl, C₃₋₁₀-cycloalkyl andC₄₋₁₀-cycloalkenyl optionally comprising 1-4 heteroatoms selected fromN, O and S and optionally substituted with one or more substituents ofR¹¹, R¹² or R¹⁶, NR¹¹R¹², NR¹²R¹², OR¹¹, SR¹¹, OR¹², SR¹², C(O)R¹¹,OC(O)R¹¹, COOR¹¹, C(O)R¹², OC(O)R¹², COOR¹², C(O)NR¹¹R¹², NR¹²C(O)R¹¹,C(O)NR¹²R¹², NR¹²C(O)R¹², NR¹²C(O)NR¹¹R¹², NR¹²C(O)NR¹²R¹²,NR¹²(COOR¹¹), NR¹²(COOR¹²), OC(O)NR¹¹R¹², OC(O)NR¹²R¹², S(O)₂R¹¹,S(O)₂R¹², S(O)₂NR¹¹R¹², S(O)₂NR¹²R¹², NR¹²S(O)₂NR¹¹R¹²,NR¹²S(O)₂NR¹²R¹², NR¹²S(O)₂R¹¹, NR¹²S(O)₂R¹², NR¹²S(O)₂R¹¹ orNR¹²S(O)₂R¹²;

R¹¹ is a phenyl, naphthyl, 5,6,7,8-tetrahydronaphthyl, dihydro-indenyl,pyridyl, pyrimidinyl, triazinyl, quinolinyl, tetrahydroquinolinyl,oxo-tetrahydroquinolinyl, isoquinolinyl, oxo-tetrahydroisoquinolinyl,tetrahydroisoquinolinyl, quinazolinyl, isoquinazolinyl, thiophenyl,furyl, tetrahydrofuranyl, pyrrolyl, pyrazolyl, thieno-pyrazolyl,tetrahydropentapyrazolyl, imidazolyl, triazolyl, tetrazolyl, thiazolyl,thiadiazolyl, benzothiazolyl, oxazolyl, oxadiazolyl, benzoxazolyl,benzoxadiazolyl, isoxazolyl, isothiazolyl, indolyl, azaindolyl,2,3-dihydroindolyl, isoindolyl, indazolyl, benzofuranyl,benzothiophenyl, benzimidazolyl, imidazopyridinyl, purinyl,benzotriazolyl, oxazolinyl, isoxazolinyl, thiazolinyl, pyrrolidinyl,pyrazolinyl, morpholinyl, piperidinyl, piperazinyl, pyranyl, dioxozinyl,2,3-dihydro-1,4-benzoxazinyl, 1,3-benzodioxolyl, cyclopropyl,cyclobutyl, azetidinyl, cyclopentyl, cyclohexyl or cycloheptyl ringsystem, said ring system optionally substituted independently with 1-3substituents of R¹², R¹³, R¹⁴ or R¹⁶;

alternatively, R¹⁰ and R¹¹ taken together form a partially or fullysaturated or unsaturated 5-6 membered ring of carbon atoms optionallyincluding 1-3 heteroatoms selected from O, N, or S, and the ringoptionally substituted independently with 1-3 substituents of R¹², R¹³,R¹⁴ or R¹⁶;

R¹² is H, C₁₋₁₀-alkyl, C₂₋₁₀-alkenyl, C₂₋₁₀-alkynyl, C₃₋₁₀-cycloalkyl,C₄₋₁₀-cycloalkenyl, C₁₋₁₀-alkylamino-, C₁₋₁₀-dialkylamino-,C₁₋₁₀-alkoxyl or C₁₋₁₀-thioalkyl, each of which is optionallysubstituted independently with 1-3 substituents of R¹³, R¹⁴, R¹⁵ or R¹⁶;

R¹³ is NR¹⁴R¹⁵, NR¹⁵R¹⁵, OR¹⁴; SR¹⁴, OR¹⁵; SR¹⁵, C(O)R¹⁴, OC(O)R¹⁴,COOR¹⁴, C(O)R¹⁵, OC(O)R¹⁵, COOR¹⁵, C(O)NR¹⁴R¹⁵, C(O)NR¹⁵R¹⁵,NR¹⁴C(O)R¹⁴, NR¹⁵C(O)R¹⁴, NR¹⁴C(O)R¹⁵, NR¹⁵C(O)R¹⁵, NR¹⁵C(O)NR¹⁴R¹⁵,NR¹⁵C(O)NR¹⁵R¹⁵, NR¹⁵(COOR¹⁴), NR¹⁵(COOR¹⁵), OC(O)NR¹⁴R¹⁵, OC(O)NR¹⁵R¹⁵,S(O)₂R¹⁴, S(O)₂R¹⁵, S(O)₂NR¹⁴R¹⁵, S(O)₂NR¹⁵R¹⁵, NR¹⁴S(O)₂NR¹⁴R¹⁵,NR¹⁵S(O)₂NR¹⁵R¹⁵, NR¹⁴S(O)₂R¹⁴ or NR¹⁵S(O)₂R¹⁵;

R¹⁴ is phenyl, pyridyl, pyrimidinyl, thiophenyl, furyl, tetrahydrofuryl,pyrrolyl, pyrazolyl, thieno-pyrazolyl, imidazolyl, triazolyl, thiazolyl,thiadiazolyl, benzothiazolyl, oxazolyl, oxadiazolyl, benzoxazolyl,benzoxadiazolyl, isoxazolyl, isothiazolyl, indolyl, azaindolyl,isoindolyl, indazolyl, benzofuranyl, benzothiophenyl, benzimidazolyl,pyrrolidinyl, pyrazolinyl, morpholinyl, piperidinyl, piperazinyl,2,3-dihydro-1,4-benzoxazinyl, 1,3-benzodioxolyl, cyclopropyl,cyclobutyl, azetidinyl, cyclopentyl and cyclohexyl, each of which isoptionally substituted independently with 1-3 substituents of R¹⁵ orR¹⁶;

R¹⁵ is H or C₁₋₁₀-alkyl, C₂₋₁₀-alkenyl, C₂₋₁₀-alkynyl, C₃₋₁₀-cycloalkyl,C₄₋₁₀-cycloalkenyl, C₁₋₁₀-alkylamino-, C₁₋₁₀-dialkylamino-,C₁₋₁₀-alkoxyl or C₁₋₁₀-thioalkoxyl, each of which is optionallysubstituted independently with 1-5 substituents of R¹⁶; and

R¹⁶ is H, halo, haloalkyl, CN, OH, NO₂, NH₂, OH, methyl, methoxyl,ethyl, ethoxyl, propyl, propoxyl, isopropyl, cyclopropyl, butyl,isobutyl, tert-butyl, methylamino, dimethylamino, ethylamino,diethylamino, isopropylamino, oxo, acetyl, benzyl, phenyl, cyclopropyl,cyclobutyl or a partially or fully saturated or unsaturated 5-8 memberedmonocyclic or 6-12 membered bicyclic ring system, said ring systemformed of carbon atoms optionally including 1-3 heteroatoms ifmonocyclic or 1-6 heteroatoms if bicyclic, said heteroatoms selectedfrom O, N, or S, and optionally substituted independently with 1-5substituents of halo, haloalkyl, CN, NO₂, NH₂, OH, methyl, methoxyl,ethyl, ethoxyl, propyl, propoxyl, isopropyl, cyclopropyl, butyl,isobutyl, tert-butyl, methylamino, dimethylamino, ethylamino,diethylamino, isopropylamino, benzyl or phenyl.

In another embodiment, the compounds are generally defined by FormulaII, wherein:

R² is

wherein

R^(3a) is COOR¹⁰, COOR¹¹, C(O)SR¹⁰, C(O)SR¹¹, C(O)NR¹⁰R¹⁰, C(O)NR¹⁰R¹¹,NR¹⁰R¹¹, NR¹⁰C(O)R¹⁰, NR¹⁰C(O)R¹¹, S(O)₂NR¹⁰R¹⁰, S(O)₂NR¹⁰R¹¹,NR¹⁰S(O)₂NR¹⁰R¹¹, NR¹⁰S(O)₂R¹⁰ or NR¹⁰S(O)₂R¹¹;

each of R^(3b), R^(3c) and R^(3d), independently, is H, F, Cl, Br, I,CF₃, CF₂CF₃, OCF₃, OCF₂CF₃, CN, NO₂, NH₂, methyl, ethyl, propyl,isopropyl, n-butyl, sec-butyl, tert-butyl, acetylenyl, cyclopropyl,cyclobutyl, cyclopentyl, cyclohexyl, OH, methoxyl, ethoxyl, propoxyl,SH, thiomethyl or thioethyl;

each of R⁴ and R⁵, independently, is H, F, Cl, Br, I, CF₃, CF₂CF₃, OCF₃,CN, methyl, ethyl, propyl, isopropyl, n-butyl, sec-butyl, tert-butyl,OH, methoxyl, ethoxyl, propoxyl;

each R⁷, independently, is H, C(O)R⁸, COOR⁸, C(O)R⁹, COOR⁹, C(O)NR⁸R⁹,C(O)NR⁹R⁹, S(O)₂R⁸, S(O)₂NR⁸R⁹, S(O)₂R⁹, S(O)₂NR⁹R⁹, C₁₋₁₀-alkyl,C₂₋₁₀-alkenyl, C₂₋₁₀-alkynyl or C₃₋₁₀-cycloalkyl, each of theC₁₋₁₀-alkyl, C₂₋₁₀-alkenyl, C₂₋₁₀-alkynyl and C₃₋₁₀-cycloalkyloptionally comprising 1-4 heteroatoms selected from N, O and S andoptionally substituted with one or more substituents of NR⁸R⁹, NR⁹R⁹,OR⁸, SR⁸, OR⁹, SR⁹, C(O)R⁸, C(O)R⁹, C(O)NR⁸R⁹, C(O)NR⁹R⁹, NR⁹C(O)R⁸,NR⁹C(O)R⁹, NR⁹C(O)NR⁸R⁹, NR⁹C(O)NR⁹R⁹, NR⁹(COOR⁸), NR⁹(COOR⁹), S(O)₂R⁸,S(O)₂NR⁸R⁹, S(O)₂R⁹, S(O)₂NR⁹R⁹, NR⁹S(O)₂NR⁸R⁹, NR⁹S(O)₂NR⁹R⁹,NR⁹S(O)₂R⁸, NR⁹S(O)₂R⁹, R⁸ or R⁹;

R⁸ is a phenyl, naphthyl, pyridyl, piperazinyl, triazinyl, quinolinyl,isoquinolinyl, quinazolinyl, isoquinazolinyl, thiophenyl, furyl,pyrrolyl, imidazolyl, triazolyl, thiazolyl, oxazolyl, isoxazolyl,isothiazolyl, indolyl, isoindolyl, benzofuranyl, benzothiophenyl,benzimidazolyl, tetrahydrofuranyl, pyrrolidinyl, oxazolinyl,isoxazolinyl, thiazolinyl, pyrazolinyl, morpholinyl, piperidinyl,piperazinyl, pyranyl, dioxozinyl, cyclopropyl, cyclobutyl, cyclopentyl,cyclohexyl or cycloheptyl ring system, said ring system optionallysubstituted independently with 1-3 substituents of R⁹, oxo, NR⁹R⁹, OR⁹;SR⁹, C(O)R⁹, phenyl, pyridyl, piperidyl, piperazinyl or morpholinyl;

R⁹ is H, halo, haloalkyl, CN, OH, NO₂, NH₂, acetyl, C₁₋₁₀-alkyl,C₂₋₁₀-alkenyl, C₂₋₁₀-alkynyl, C₃₋₁₀-cycloalkyl, C₁₋₁₀-alkylamino-,C₁₋₁₀-dialkylamino-, C₁₋₁₀-alkoxyl, C₁₋₁₀-thioalkoxyl or a ring systemselected from phenyl, naphthyl, pyridyl, piperazinyl, triazinyl,quinolinyl, isoquinolinyl, quinazolinyl, isoquinazolinyl, thiophenyl,furyl, pyrrolyl, imidazolyl, triazolyl, thiazolyl, oxazolyl, isoxazolyl,isothiazolyl, indolyl, isoindolyl, benzofuranyl, benzothiophenyl,benzimidazolyl, tetrahydrofuranyl, pyrrolidinyl, oxazolinyl,isoxazolinyl, thiazolinyl, pyrazolinyl, morpholinyl, piperidinyl,piperazinyl, pyranyl and dioxozinyl, each of the C₁₋₁₀-alkyl,C₂₋₁₀-alkenyl, C₂₋₁₀-alkynyl, C₃₋₁₀-cycloalkyl, C₁₋₁₀-alkylamino-,C₁₋₁₀-dialkylamino-, C₁₋₁₀-alkoxyl, C₁₋₁₀-thioalkoxyl and ring systemoptionally substituted independently with 1-3 substituents of halo,haloalkyl, CN, NO₂, NH₂, OH, oxo, methyl, methoxyl, ethyl, ethoxyl,propyl, propoxyl, isopropyl, cyclopropyl, butyl, isobutyl, tert-butyl,methylamino, dimethylamino, ethylamino, diethylamino, propylamine,isopropylamine, dipropylamine, diisopropylamine, benzyl or phenyl;

R¹⁰ is H, methyl, ethyl, propyl, isopropyl, n-butyl, sec-butyl,tert-butyl, acetylenyl, cyclopropyl, cyclobutyl, cyclopentyl,cyclohexyl, OH, methoxyl, ethoxyl, propoxyl, SH, thiomethyl orthioethyl; each of which is optionally substituted with one or moresubstituents of R¹¹, R¹² or R¹⁶;

R¹¹ is a phenyl, naphthyl, 5,6,7,8-tetrahydronaphthyl, dihydro-indenyl,pyridyl, pyrimidinyl, triazinyl, quinolinyl, tetrahydroquinolinyl,oxo-tetrahydroquinolinyl, isoquinolinyl, oxo-tetrahydroisoquinolinyl,tetrahydroisoquinolinyl, quinazolinyl, isoquinazolinyl, thiophenyl,furyl, tetrahydrofuranyl, pyrrolyl, pyrazolyl, thieno-pyrazolyl,tetrahydropentapyrazolyl, imidazolyl, triazolyl, tetrazolyl, thiazolyl,thiadiazolyl, benzothiazolyl, oxazolyl, oxadiazolyl, benzoxazolyl,benzoxadiazolyl, isoxazolyl, isothiazolyl, indolyl, azaindolyl,2,3-dihydroindolyl, isoindolyl, indazolyl, benzofuranyl,benzothiophenyl, benzimidazolyl, imidazopyridinyl, purinyl,benzotriazolyl, oxazolinyl, isoxazolinyl, thiazolinyl, pyrrolidinyl,pyrazolinyl, morpholinyl, piperidinyl, piperazinyl, pyranyl, dioxozinyl,2,3-dihydro-1,4-benzoxazinyl, 1,3-benzodioxolyl, cyclopropyl,cyclobutyl, azetidinyl, cyclopentyl, cyclohexyl or cycloheptyl ringsystem, said ring system optionally substituted independently with 1-3substituents of R¹², R¹³, R¹⁴ or R¹⁶;

alternatively, R¹⁰ and R¹¹ taken together form a partially or fullysaturated or unsaturated 5-6 membered ring of carbon atoms optionallyincluding 1-3 heteroatoms selected from O, N, or S, and the ringoptionally substituted independently with 1-3 substituents of R¹², R¹³,R¹⁴ or R¹⁶;

R¹² is H, C₁₋₁₀-alkyl, C₂₋₁₀-alkenyl, C₂₋₁₀-alkynyl, C₃₋₁₀-cycloalkyl,C₄₋₁₀-cycloalkenyl, C₁₋₁₀-alkylamino-, C₁₋₁₀-dialkylamino-,C₁₋₁₀-alkoxyl or C₁₋₁₀-thioalkyl, each of which is optionallysubstituted independently with 1-3 substituents of R¹³, R¹⁴, R¹⁵ or R¹⁶;

R¹³ is NR¹⁴R¹⁵, NR¹⁵R¹⁵, OR¹⁴; SR¹⁴, OR¹⁵; SR¹⁵, C(O)R¹⁴, OC(O)R¹⁴,COOR¹⁴, C(O)R¹⁵, OC(O)R¹⁵, COOR¹⁵, C(O)NR¹⁴R¹⁵, C(O)NR¹⁵R¹⁵,NR¹⁴C(O)R¹⁴, NR¹⁵C(O)R¹⁴, NR¹⁴C(O)R¹⁵, NR¹⁵C(O)R¹⁵, NR¹⁵C(O)NR¹⁴R¹⁵,NR¹⁵C(O)NR¹⁵R¹⁵, NR¹⁵(COOR¹⁴), NR¹⁵ (COOR¹⁵), OC(O)NR¹⁴R¹⁵,OC(O)NR¹⁵R¹⁵, S(O)₂R¹⁴, S(O)₂R¹⁵, S(O)₂NR¹⁴R¹⁵, S(O)₂NR¹⁵R¹⁵,NR¹⁴S(O)₂NR¹⁴R¹⁵, NR¹⁵S(O)₂NR¹⁵R¹⁵, NR¹⁴S(O)₂R¹⁴ or NR¹⁵S(O)₂R¹⁵;

R¹⁴ is phenyl, pyridyl, pyrimidinyl, thiophenyl, furyl, tetrahydrofuryl,pyrrolyl, pyrazolyl, thieno-pyrazolyl, imidazolyl, triazolyl, thiazolyl,thiadiazolyl, benzothiazolyl, oxazolyl, oxadiazolyl, benzoxazolyl,benzoxadiazolyl, isoxazolyl, isothiazolyl, indolyl, azaindolyl,isoindolyl, indazolyl, benzofuranyl, benzothiophenyl, benzimidazolyl,pyrrolidinyl, pyrazolinyl, morpholinyl, piperidinyl, piperazinyl,2,3-dihydro-1,4-benzoxazinyl, 1,3-benzodioxolyl, cyclopropyl,cyclobutyl, azetidinyl, cyclopentyl and cyclohexyl, each of which isoptionally substituted independently with 1-3 substituents of R¹⁵ orR¹⁶;

R¹⁵ is H or C₁₋₁₀-alkyl, C₂₋₁₀-alkenyl, C₂₋₁₀-alkynyl, C₃₋₁₀-cycloalkyl,C₄₋₁₀-cycloalkenyl, C₁₋₁₀-alkylamino-, C₁₋₁₀-dialkylamino-,C₁₋₁₀-alkoxyl or C₁₋₁₀-thioalkoxyl, each of which is optionallysubstituted independently with 1-3 substituents of R¹⁶; and

R¹⁶ is H, halo, haloalkyl, CN, OH, NO₂, NH₂, OH, methyl, methoxyl,ethyl, ethoxyl, propyl, propoxyl, isopropyl, cyclopropyl, butyl,isobutyl, tert-butyl, methylamino, dimethylamino, ethylamino,diethylamino, isopropylamino, oxo, acetyl, benzyl, phenyl, cyclopropyl,cyclobutyl or a partially or fully saturated or unsaturated 5-8 memberedmonocyclic or 6-12 membered bicyclic ring system, said ring systemformed of carbon atoms optionally including 1-3 heteroatoms ifmonocyclic or 1-6 heteroatoms if bicyclic, said heteroatoms selectedfrom O, N, or S, and optionally substituted independently with 1-5substituents of halo, haloalkyl, CN, NO₂, NH₂, OH, methyl, methoxyl,ethyl, ethoxyl, propyl, propoxyl, isopropyl, cyclopropyl, butyl,isobutyl, tert-butyl, methylamino, dimethylamino, ethylamino,diethylamino, isopropylamino, benzyl or phenyl.

In another embodiment, the compounds are generally defined by Formula II

wherein

R² is a phenyl, naphthyl, pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl,triazinyl, thiophenyl, furyl, pyrrolyl, imidazolyl, triazolyl,thiazolyl, oxazolyl, isoxazolyl, isothiazolyl, indolyl or isoindolylring system, said ring system substituted independently with 0-3substituents of R¹⁰, R¹¹ or R¹⁵ and one substituent, meta or para to thepoint of attachment of the alkyne on the R² ring, is NR¹⁰C(O)NR¹⁰R¹⁰,NR¹⁰C(O)NR¹⁰R¹¹, NR¹⁰(COOR¹⁰) or NR¹⁰(COOR¹¹);

R⁷ is H, C₁₋₁₀-alkyl or C₃₋₁₀-cycloalkyl, each of the C₁₋₁₀-alkyl andC₃₋₁₀-cycloalkyl optionally comprising 1-2 heteroatoms selected from N,O and S and optionally substituted with 1-3 substituents of R⁹;

R⁸ is a phenyl, naphthyl, pyridyl, pyrimidinyl, pyrrolidinyl,piperidinyl, piperazinyl, quinolinyl, isoquinolinyl,tetrahydroquinolinyl, tetrahydroisoquinolinyl, quinazolinyl,isoquinazolinyl, tetrahydroquinazolinyl, tetrahydroisoquinazolinyl,morpholinyl, thiophenyl, furyl, dihydrofuryl, tetrahydrofuryl, pyrrolyl,imidazolyl, thiazolyl, oxazolyl, isoxazolyl, isothiazolyl, indolyl,isoindolyl, indolinyl, benzofuranyl, dihydrobenzofuranyl,benzothiophenyl or benzimidazolyl ring system, said ring systemoptionally substituted independently with 1-3 substituents of R⁹, oxo,NR⁹R⁹, OR⁹; SR⁹, C(O)R⁹ or a partially or fully saturated or unsaturated5-6 membered ring of carbon atoms optionally including 1-3 heteroatomsselected from O, N, or S, and optionally substituted independently with1-3 substituents of R⁹;

alternatively, R⁷ and R⁸ taken together form a 5-6 membered ringselected from pyrrolidine, piperidine, morpholine and piperazine, thering optionally substituted independently with 1-3 substituents of R⁹;

R⁹ is H, halo, haloalkyl, CN, OH, NO₂, NH₂, acetyl, C₁₋₁₀-alkyl,C₂₋₁₀-alkenyl, C₂₋₁₀-alkynyl, C₃₋₁₀-cycloalkyl, C₁₋₁₀-alkylamino-,C₁₋₁₀-dialkylamino-, C₁₋₁₀-alkoxyl, C₁₋₁₀-thioalkoxyl or a ring systemof phenyl, naphthyl, pyridyl, pyrimidinyl, pyrrolidinyl, piperidinyl,piperazinyl, quinolinyl, isoquinolinyl, tetrahydroquinolinyl,tetrahydroisoquinolinyl, quinazolinyl, isoquinazolinyl,tetrahydroquinazolinyl, tetrahydroisoquinazolinyl, morpholinyl,thiophenyl, furyl, dihydrofuryl, tetrahydrofuryl, pyrrolyl, imidazolyl,thiazolyl, oxazolyl, isoxazolyl, isothiazolyl, indolyl, isoindolyl,indolinyl, benzofuranyl, dihydrobenzofuranyl, benzothiophenyl andbenzimidazolyl, wherein each of the C₁₋₁₀-alkyl, C₂₋₁₀-alkenyl,C₂₋₁₀-alkynyl, C₃₋₁₀-cycloalkyl, C₄₋₁₀-cycloalkenyl, C₁₋₁₀-alkylamino-,C₁₋₁₀-dialkylamino-, C₁₋₁₀-alkoxyl, C₁₋₁₀-thioalkoxyl and ring system isoptionally substituted independently with 1-3 substituents of halo,haloalkyl, CN, NO₂, NH₂, OH, oxo, methyl, methoxyl, ethyl, ethoxyl,propyl, propoxyl, isopropyl, cyclopropyl, butyl, isobutyl, tert-butyl,methylamine, dimethylamine, ethylamine, diethylamine, propylamine,isopropylamine, dipropylamine, diisopropylamine, benzyl or phenyl;

R¹⁰ is H, C₁₋₁₀-alkyl, C₂₋₁₀-alkenyl, C₂₋₁₀-alkynyl or C₃₋₁₀-cycloalkyl,each of the C₁₋₁₀-alkyl, C₂₋₁₀-alkenyl, C₂₋₁₀-alkynyl andC₃₋₁₀-cycloalkyl optionally comprising 1-4 heteroatoms selected from N,O and S and optionally substituted with 1-3 substituents of R¹¹, R¹² orR¹⁶, NR¹¹R¹², NR¹²R¹², OR¹¹, SR¹¹, OR¹², SR¹², C(O)R¹¹, OC(O)R¹¹,COOR¹¹, C(O)R¹², O(O)R¹², COOR¹², C(O)NR¹¹R¹², NR¹²C(O)R¹¹, C(O)NR¹²R¹²,NR¹²C(O)R¹², NR¹²C(O)NR¹¹R¹², NR¹²C(O)NR¹²R¹², NR¹²(COOR¹¹),NR¹²(COOR¹²), OC(O)NR¹¹R¹², OC(O)NR¹²R¹², S(O)₂R¹¹, S(O)₂R¹²,S(O)₂NR¹¹R¹², S(O)₂NR¹²R¹², NR¹²S(O)₂NR¹¹R¹², NR¹²S(O)₂NR¹²R¹²,NR¹²S(O)₂R¹¹, NR¹²S(O)₂R¹², NR¹²S(O)₂R¹¹ or NR¹²S(O)₂R¹²;

R¹¹ is a phenyl, naphthyl, pyridyl, pyrimidinyl, quinolinyl,isoquinolinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl,quinazolinyl, isoquinazolinyl, tetrahydroquinazolinyl,tetrahydroisoquinazolinyl, thiophenyl, furyl, pyrrolyl, imidazolyl,thiazolyl, oxazolyl, isoxazolyl, isothiazolyl, indolyl, isoindolyl,indolinyl, benzofuranyl, dihydrobenzofuranyl, benzothiophenyl orbenzimidazolyl ring system, said ring system optionally substitutedindependently with 1-3 substituents of R¹², R¹³, R¹⁴ or R¹⁶;

alternatively, R¹⁰ and R¹¹ taken together form a partially or fullysaturated or unsaturated 5-6 membered ring of carbon atoms optionallyincluding 1-3 heteroatoms selected from O, N, or S, said ring optionallysubstituted independently with 1-3 substituents of R¹², R¹³, R¹⁴ or R¹⁶;

R¹² is H, C₁₋₁₀-alkyl, C₂₋₁₀-alkenyl, C₂₋₁₀-alkynyl, C₃₋₁₀-cycloalkyl,C₄₋₁₀-cycloalkenyl, C₁₋₁₀-alkylamino-, C₁₋₁₀-dialkylamino-,C₁₋₁₀-alkoxyl or C₁₋₁₀-thioalkyl, each of which is optionallysubstituted independently with 1-3 substituents of R¹³, R¹⁴, R¹⁵ or R¹⁶;

R¹³ is NR¹⁴R¹⁵, NR¹⁵R¹⁵, OR¹⁴; SR¹⁴, OR¹⁵; SR¹⁵, C(O)R¹⁴, OC(O)R¹⁴,COOR¹⁴, C(O)R¹⁵, OC(O)R¹⁵, COOR¹⁵, C(O)NR¹⁴R¹⁵, C(O)NR¹⁵R¹⁵,NR¹⁴C(O)R¹⁴, NR¹⁵C(O)R¹⁴, NR¹⁴C(O)R¹⁵, NR¹⁵(COOR¹⁵), NR¹⁵C(O)NR¹⁴R¹⁵,NR¹⁵C(O)NR¹⁵R¹⁵, NR¹⁵(COOR¹⁴), NR¹⁵(COOR¹⁵, OC(O)NR¹⁴R¹⁵, OC(O)NR¹⁵R¹⁵,S(O)₂R¹⁴, S(O)₂R¹⁵, S(O)₂NR¹⁴R¹⁵, S(O)₂NR¹⁵R¹⁵, NR¹⁴S(O)₂NR¹⁴R¹⁵,NR¹⁵S(O)₂NR¹⁵R¹⁵, NR¹⁴S(O)₂R¹⁴ or NR¹⁵S(O)₂R¹⁵;

R¹⁴ is phenyl, naphthyl, pyridyl, pyrimidinyl, pyrrolidinyl,piperidinyl, piperazinyl, quinolinyl, isoquinolinyl,tetrahydroquinolinyl, tetrahydroisoquinolinyl, quinazolinyl,isoquinazolinyl, tetrahydroquinazolinyl, tetrahydroisoquinazolinyl,morpholinyl, thiophenyl, furyl, dihydrofuryl, tetrahydrofuryl, pyrrolyl,imidazolyl, thiazolyl, oxazolyl, isoxazolyl, isothiazolyl, indolyl,isoindolyl, indolinyl, benzofuranyl, dihydrobenzofuranyl, benzoxazinyl,benzodioxazinyl, benzothiophenyl and benzimidazolyl, each of which isoptionally substituted independently with 1-5 substituents of R¹⁵ orR¹⁶;

R¹⁵ is H or C₁₋₁₀-alkyl, C₂₋₁₀-alkenyl, C₂₋₁₀-alkynyl, C₃₋₁₀-cycloalkyl,C₄₋₁₀-cycloalkenyl, C₁₋₁₀-alkylamino-, C₁₋₁₀-dialkylamino-,C₁₋₁₀-alkoxyl or C₁₋₁₀-thioalkoxyl, each of which is optionallysubstituted independently with 1-5 substituents of R¹⁶; and

R¹⁶ is H, halo, haloalkyl, CN, OH, NO₂, NH₂, OH, methyl, methoxyl,ethyl, ethoxyl, propyl, propoxyl, isopropyl, cyclopropyl, butyl,isobutyl, tert-butyl, methylamino, dimethylamino, ethylamino,diethylamino, isopropylamino, oxo, acetyl, benzyl, phenyl, cyclopropyl,cyclobutyl or a partially or fully saturated or unsaturated 5-8 memberedmonocyclic or 6-12 membered bicyclic ring system, said ring systemformed of carbon atoms optionally including 1-3 heteroatoms ifmonocyclic or 1-6 heteroatoms if bicyclic, said heteroatoms selectedfrom O, N, or S, and optionally substituted independently with 1-5substituents of halo, haloalkyl, CN, NO₂, NH₂, OH, methyl, methoxyl,ethyl, ethoxyl, propyl, propoxyl, isopropyl, cyclopropyl, butyl,isobutyl, tert-butyl, methylamino, dimethylamino, ethylamino,diethylamino, isopropylamino, benzyl or phenyl.

In another embodiment, the compounds are generally defined by Formula Iwherein

A¹ and A⁴, independently, are N;

A² is CR⁴;

A³ is CR⁵;

R¹ is SR⁷, OR⁸, SR⁸, C(O)R⁷, OC(O)R⁷, COOR⁷, C(O)R⁸, OC(O)R⁸, COOR⁸,C(O)NR⁷R⁷, C(S)NR⁷R⁷, NR⁷C(O)R⁷, NR⁷C(S)R⁷, NR⁷C(O)NR⁷R⁷, NR⁷C(S)NR⁷R⁷,NR⁷(COOR⁷), OC(O)NR⁷R⁷, C(O)NR⁷R⁸, C(S)NR⁷R⁸, NR⁷C(O)R⁸, NR⁷C(S)R⁸,NR⁷C(O)NR⁷R⁸, NR⁷C(S)NR⁷R⁸, NR⁷(COOR⁸), OC(O)NR⁷R⁸, S(O)₂R⁷, S(O)₂NR⁷R⁷,NR⁷S(O)₂NR⁷R⁷, NR⁷S(O)₂R⁷, S(O)₂R⁸, S(O)₂NR⁷R⁸, NR⁷S(O)₂NR⁷R⁸ orNR⁷S(O)₂R⁸;

R² is a phenyl, naphthyl, pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl,triazinyl, quinolinyl, isoquinolinyl, quinazolinyl, isoquinazolinyl,phthalazinyl, aza-phthalazinyl, thiophenyl, furyl, pyrrolyl, imidazolyl,pyrazolyl, triazolyl, thiazolyl, thiadiazolyl, oxazolyl, isoxazolyl,oxadiazolyl, isothiazolyl, indolyl, isoindolyl, benzofuranyl,dihydrobenzofuranyl, benzothiophenyl or benzimidazolyl ring system, saidring system substituted independently with 1-5 substituents of R¹⁰, R¹¹,R¹⁵, NR¹⁰R¹⁰, NR¹⁰R¹¹, OR¹⁰, SR¹⁰, OR¹¹, SR¹¹, C(O)R¹⁰, C(S)R¹⁰,C(NCN)R¹⁰, C(O)R¹¹, C(S)R¹¹, C(NCN)R¹¹, C(O)C(O)R¹⁰, OC(O)R¹⁰, COOR¹⁰,C(O)SR¹⁰, C(O)C(O)R¹¹, OC(O)R¹¹, COOR¹¹, C(O)SR¹¹, C(O)NR¹⁰R¹⁰,C(S)NR¹⁰R¹⁰, C(O)NR¹⁰R¹¹, C(S)NR¹⁰R¹¹, OC(O)NR¹⁰R¹¹, NR¹⁰C(O)R¹⁰,NR¹⁰C(O)R¹¹, NR¹⁰C(S)R¹⁰, NR¹⁰C(S)R¹¹, NR¹⁰C(O)NR¹⁰R¹⁰, NR¹⁰C(O)NR¹⁰R¹¹,NR¹⁰C(S)NR¹⁰R¹⁰, NR¹⁰C(S)NR¹⁰R¹¹, NR¹⁰(COOR¹⁰), NR¹⁰(COOR¹¹),NR¹⁰C(O)C(O)R¹⁰, NR¹⁰C(O)C(O)R¹¹, NR¹⁰C(O)C(O)NR¹⁰R¹¹, S(O)₂R¹⁰,S(O)₂R¹¹, S(O)₂NR¹⁰R¹⁰, S(O)₂NR¹⁰R¹¹, NR¹⁰S(O)₂NR¹⁰R¹¹, NR¹⁰S(O)₂R¹⁰ orNR¹⁰S(O)₂R¹¹, provided that (1) one substituent is C(O)R¹⁰, COOR¹⁰,C(O)R¹¹, COOR¹¹, C(O)NR¹⁰R¹⁰, C(S)NR¹⁰R¹⁰, C(O)NR¹⁰R¹¹, C(S)NR¹⁰R¹¹,NR¹⁰C(O)R¹⁰, NR¹⁰C(S)R¹⁰, NR¹⁰C(O)R¹¹, NR¹⁰C(S)R¹¹, NR¹⁰C(O)NR¹⁰R¹⁰,NR¹⁰C(O)NR¹⁰R¹¹, NR¹⁰(COOR¹⁰), NR¹⁰(COOR¹¹), NR¹⁰C(S)NR¹⁰R¹¹,NR¹⁰C(S)NR¹⁰R¹¹, S(O)₂NR¹⁰R¹⁰, S(O)₂NR¹⁰R¹¹, NR¹⁰S(O)₂NR¹⁰R¹¹,NR¹⁰S(O)₂R¹⁰ or NR¹⁰S(O)₂R¹¹;

R⁴ is H, halo, haloalkyl, NO₂, CN, NR⁷R⁷, OR⁷, SR⁷, C(O)R⁷, C₁₋₁₀-alkyl,C₂₋₁₀-alkenyl, C₂₋₁₀-alkynyl or C₃₋₁₀-cycloalkyl, each of theC₁₋₁₀-alkyl, C₂₋₁₀-alkenyl, C₂₋₁₀-alkynyl and C₃₋₁₀-cycloalkyloptionally comprising 1-4 heteroatoms selected from N, O and S andoptionally substituted with 1-3 substituents of R⁹;

R⁵ is H, halo, haloalkyl, NO₂, CN, NR⁷R⁷, OR⁷; SR⁷, C(O)R⁷, C₁₋₁₀-alkyl,C₂₋₁₀-alkenyl, C₂₋₁₀-alkynyl or C₃₋₁₀-cycloalkyl, each of theC₁₋₁₀-alkyl, C₂₋₁₀-alkenyl, C₂₋₁₀-alkynyl and C₃₋₁₀-cycloalkyloptionally comprising 1-4 heteroatoms selected from N, O and S andoptionally substituted with 1-3 substituents of R⁹;

R⁷ is H, C₁₋₁₀-alkyl, C₂₋₁₀-alkenyl, C₂₋₁₀-alkynyl, C₃₋₁₀-cycloalkyl orC₄₋₁₀-cycloalkenyl, each of the C₁₋₁₀-alkyl, C₂₋₁₀-alkenyl,C₂₋₁₀-alkynyl, C₃₋₁₀-cycloalkyl and C₄₋₁₀-cycloalkenyl optionallycomprising 1-4 heteroatoms selected from N, O and S and optionallysubstituted with 1-3 substituents of NR⁸R⁹, NR⁹R⁹, OR⁸, SR⁸, OR⁹, SR⁹,C(O)R⁸, OC(O)R⁸, COOR⁸, C(O)R⁹, OC(O)R⁹, COOR⁹, C(O)NR⁸R⁹, C(O)NR⁹R⁹,NR⁹C(O)R⁸, NR⁹C(O)R⁹, NR⁹C(O)NR⁸R⁹, NR⁹C(O)NR⁹R⁹, NR⁹(COOR⁸),NR⁹(COOR⁹), OC(O)NR⁸R⁹, OC(O)NR⁹R⁹, S(O)₂R⁸, S(O)₂NR⁸R⁹, S(O)₂R⁹,S(O)₂NR⁹R⁹, NR⁹S(O)₂NR⁸R⁹, NR⁹S(O)₂NR⁹R⁹, NR⁹S(O)₂R⁸, NR⁹S(O)₂R⁹, R⁸ orR⁹;

R⁸ is a partially or fully saturated or unsaturated 5-8 memberedmonocyclic, 6-12 membered bicyclic, or 7-14 membered tricyclic ringsystem, said ring system formed of carbon atoms optionally including 1-3heteroatoms if monocyclic, 1-6 heteroatoms if bicyclic, or 1-9heteroatoms if tricyclic, said heteroatoms selected from O, N, or S, andwherein said ring system is optionally substituted independently with1-5 substituents of R⁹, oxo, NR⁹R⁹, OR⁹; SR⁹, C(O)R⁹ or a partially orfully saturated or unsaturated 5-6 membered ring of carbon atomsoptionally including 1-3 heteroatoms selected from O, N, or S, andoptionally substituted independently with 1-3 substituents of R⁹;

alternatively, R⁷ and R⁸ taken together form a saturated or partially orfully unsaturated 5-6 membered ring of carbon atoms optionally including1-3 heteroatoms selected from O, N, or S, and the ring optionallysubstituted independently with 1-3 substituents of R⁹;

R⁹ is H, halo, haloalkyl, CN, OH, NO₂, NH₂, acetyl, C₁₋₁₀-alkyl,C₂₋₁₀-alkenyl, C₂₋₁₀-alkynyl, C₃₋₁₀-cycloalkyl, C₄₋₁₀-cycloalkenyl,C₁₋₁₀-alkylamino-, C₁₋₁₀-dialkylamino-, C₁₋₁₀-alkoxyl, C₁₋₁₀-thioalkoxylor a saturated or partially or fully unsaturated 5-8 membered monocyclicor a 6-12 membered bicyclic, said ring system formed of carbon atomsoptionally including 1-3 heteroatoms if monocyclic or 1-6 heteroatoms ifbicyclic, said heteroatoms selected from O, N, or S, wherein each of theC₁₋₁₀-alkyl, C₂₋₁₀-alkenyl, C₂₋₁₀-alkynyl, C₃₋₁₀-cycloalkyl,C₄₋₁₀-cycloalkenyl, C₁₋₁₀-alkylamino-, C₁₋₁₀-dialkylamino-,C₁₋₁₀-alkoxyl, C₁₋₁₀-thioalkoxyl and ring of said ring system isoptionally substituted independently with 1-3 substituents of halo,haloalkyl, CN, NO₂, NH₂, OH, oxo, methyl, methoxyl, ethyl, ethoxyl,propyl, propoxyl, isopropyl, cyclopropyl, butyl, isobutyl, tert-butyl,methylamine, dimethylamine, ethylamine, diethylamine, propylamine,isopropylamine, dipropylamine, diisopropylamine, benzyl or phenyl;

R¹⁰ is H, halo, haloalkyl, CN, NO₂, C₁₋₁₀-alkyl, C₂₋₁₀-alkenyl,C₂₋₁₀-alkynyl, C₃₋₁₀-cycloalkyl or C₄₋₁₀-cycloalkenyl, each of theC₁₋₁₀-alkyl, C₂₋₁₀-alkenyl, C₂₋₁₀-alkynyl, C₃₋₁₀-cycloalkyl andC₄₋₁₀-cycloalkenyl optionally comprising 1-4 heteroatoms selected fromN, O and S and optionally substituted with 1-5 substituents of R¹¹, R¹²or R¹⁶, NR¹¹R¹², NR¹²R¹², OR¹², SR¹¹, OR¹², SR¹², C(O)R¹¹, OC(O)R¹¹,COOR¹¹, C(O)R¹², OC(O)R¹², COOR¹², C(O)NR¹¹R¹², NR¹²C(O)R¹¹,C(O)NR¹²R¹², NR¹²C(O)R¹², NR¹²C(O)NR¹¹R¹², NR¹²C(O)NR¹²R¹², NR¹²(COOR¹¹), NR¹²(COOR¹²), OC(O)NR¹¹R¹², OC(O)NR¹²R¹², S(O)₂R¹¹, S(O)₂R¹²,S(O)₂NR¹¹R¹², S(O)₂NR¹²R¹², NR¹²S(O)₂NR¹¹R¹², NR¹²S(O)₂NR¹²R¹²,NR¹²S(O)R¹¹, NR¹²S(O)₂R¹², NR¹²S(O)₂R¹¹ or NR¹²S(O)₂R¹²;

R¹¹ is a partially or fully saturated or unsaturated 5-8 memberedmonocyclic, 6-12 membered bicyclic, or 7-14 membered tricyclic ringsystem, said ring system formed of carbon atoms optionally including 1-3heteroatoms if monocyclic, 1-6 heteroatoms if bicyclic, or 1-9heteroatoms if tricyclic, said heteroatoms selected from O, N, or S, andwherein each ring of said ring system is optionally substitutedindependently with 1-5 substituents of R¹², R¹³, R¹⁴ or R¹⁶;

alternatively, R¹⁰ and R¹¹ taken together form a partially or fullysaturated or unsaturated 5-6 membered ring of carbon atoms optionallyincluding 1-3 heteroatoms selected from O, N, or S, and the ringoptionally substituted independently with 1-5 substituents of R¹², R¹³,R¹⁴ or R¹⁶;

R¹² is H, C₁₋₁₀-alkyl, C₂₋₁₀-alkenyl, C₂₋₁₀-alkynyl, C₃₋₁₀-cycloalkyl,C₄₋₁₀-cycloalkenyl, C₁₋₁₀-alkylamino-, C₁₋₁₀-dialkylamino-,C₁₋₁₀-alkoxyl or C₁₋₁₀-thioalkyl, each of which is optionallysubstituted independently with 1-5 substituents of R¹³, R¹⁴, R¹⁵ or R¹⁶;

R¹³ is NR¹⁴R¹⁵, NR¹⁵R¹⁵, OR¹⁴; SR¹⁴, OR¹⁵; SR¹⁵, C(O)R¹⁴, OC(O)R¹⁴,COOR¹⁴, C(O)R¹⁵, OC(O)R¹⁵, COOR¹⁵, C(O)NR¹⁴R¹⁵, C(O)NR¹⁵R¹⁵,NR¹⁴C(O)R¹⁴, NR¹⁵C(O)R¹⁴, NR¹⁴C(O)R¹⁵, NR¹⁵C(O)R¹⁵, NR¹⁵C(O)NR¹⁴R¹⁵,NR¹⁵C(O)NR¹⁵R¹⁵, NR¹⁵(COOR¹⁴), NR¹⁵(COOR¹⁵), OC(O)NR¹⁴R¹⁵, OC(O)NR¹⁵R¹⁵,S(O)₂R¹⁴, S(O)₂R¹⁵, S(O)₂NR¹⁴R¹⁵, S(O)₂NR¹⁵R¹⁵, NR¹⁴S(O)₂NR¹⁴R¹⁵,NR¹⁵S(O)₂NR¹⁵R¹⁵, NR¹⁴S(O)₂R¹⁴ or NR¹⁵S(O)₂R¹⁵;

R¹⁴ is a partially or fully saturated or unsaturated 5-8 membered or asaturated or partially or fully unsaturated 5-8 membered monocyclic,6-12 membered bicyclic, or 7-14 membered tricyclic ring system, saidring system formed of carbon atoms optionally including 1-3 heteroatomsif monocyclic, 1-6 heteroatoms if bicyclic, or 1-9 heteroatoms iftricyclic, said heteroatoms selected from O, N, or S, and wherein eachring of said ring system is optionally substituted independently with1-5 substituents of R¹⁵ or R¹⁶;

R¹⁵ is H or C₁₋₁₀-alkyl, C₂₋₁₀-alkenyl, C₂₋₁₀-alkynyl, C₃₋₁₀-cycloalkyl,C₄₋₁₀-cycloalkenyl, C₁₋₁₀-alkylamino-, C₁₋₁₀-dialkylamino-,C₁₋₁₀-alkoxyl or C₁₋₁₀-thioalkoxyl, each of which is optionallysubstituted independently with 1-5 substituents of R¹⁶;

R¹⁶ is H, halo, haloalkyl, CN, OH, NO₂, NH₂, OH, methyl, methoxyl,ethyl, ethoxyl, propyl, propoxyl, isopropyl, cyclopropyl, butyl,isobutyl, tert-butyl, methylamino, dimethylamino, ethylamino,diethylamino, isopropylamino, oxo, acetyl, benzyl, phenyl, cyclopropyl,cyclobutyl or a partially or fully saturated or unsaturated 5-8 memberedmonocyclic or 6-12 membered bicyclic ring system, said ring systemformed of carbon atoms optionally including 1-3 heteroatoms ifmonocyclic or 1-6 heteroatoms if bicyclic, said heteroatoms selectedfrom O, N, or S, and optionally substituted independently with 1-5substituents of halo, haloalkyl, CN, NO₂, NH₂, OH, methyl, methoxyl,ethyl, ethoxyl, propyl, propoxyl, isopropyl, cyclopropyl, butyl,isobutyl, tert-butyl, methylamino, dimethylamino, ethylamino,diethylamino, isopropylamino, benzyl or phenyl;

and provided that (1) when said at least one substituent on said R² ringsystem is C(O)NR¹⁰R¹⁰ or C(O)NR¹⁰R¹¹, then R¹⁰ and R¹¹, independently,are not —CH₂-L-Q or —C(C₁₋₆alkyl)(C₁₋₆alkyl)-L-Q, wherein L is —O—,—NH—, —NHC(O)—, —NHC(O)N—, —NHC(═NH)N— or —CO₂— and Q is H, substitutedor unsubstituted C₁₋₆alkyl, substituted or unsubstituted aryl,substituted or unsubstituted heterocyclyl, substituted or unsubstitutedheteraryl or C₁₋₆alkyl substituted with aryl, heterocyclyl orheteroaryl; or

(2) when said R² is a phenyl ring substituted with C(O)NR¹⁰R¹⁰ orC(O)NR¹⁰R¹¹ meta to the point of attachment of the alkynyl group on R²of Formula I, then either (a) R¹ is not halogen, C₁₋₆alkyl, C₁₋₆alkoxylor hydroxyl or (b) where R¹ and R³ taken together with the atoms towhich they are attached form a partially or fully unsaturated 5- or6-membered ring of carbon atoms optionally including 1-3 heteroatomsselected from O, N, or S, said ring is not substituted with halogen,C₁₋₆alkyl, C₁₋₆alkoxyl or hydroxyl substituents.

In another embodiment, the compounds are generally defined by Formula Iherein, wherein

Each of A¹, A², A³, A⁴, R¹ are as defined in any of the embodimentsabove, and

R² is a partially or fully saturated 6-12 membered bicyclic or 7-14membered tricyclic ring system, said ring system formed of carbon atomsand including 1-6 heteroatoms if bicyclic or 1-9 heteroatoms iftricyclic, said heteroatoms selected from O, N, or S, wherein said ringsystem is substituted independently with one or more substituents ofR¹⁰, R¹¹, R¹⁵, NR¹⁰R¹⁰, NR¹⁰R¹¹, OR¹⁰, SR¹⁰, OR¹¹, SR¹¹, C(O)R¹⁰,C(S)R¹⁰, C(NCN)R¹⁰, C(O)R¹¹, C(S)R¹¹, C(NCN)R¹¹, C(O)C(O)R¹⁰, OC(O)R¹⁰,COOR¹⁰, C(O)SR¹⁰, C(O)C(O)R¹¹, OC(O)R¹¹, COOR¹¹, C(O)SR¹¹, C(O)NR¹⁰R¹⁰,C(S)NR¹⁰R¹⁰, C(O)NR¹⁰R¹¹, C(S)NR¹⁰R¹¹, OC(O)NR¹⁰R¹¹, NR¹⁰C(O)R¹⁰,NR¹⁰C(O)R¹¹, NR¹⁰C(S)R¹⁰, NR¹⁰C(S)R¹¹, NR¹⁰C(O)NR¹⁰R¹⁰, NR¹⁰C(O)NR¹⁰R¹¹,NR¹⁰C(S)NR¹⁰R¹⁰, NR¹⁰C(S)NR¹⁰R¹¹, NR¹⁰(COOR¹⁰), NR¹⁰(COOR¹¹),NR¹⁰C(O)C(O)R¹⁰, NR¹⁰C(O)C(O)R¹¹, NR¹⁰C(O)C(O)NR¹⁰R¹¹, S(O)₂R¹⁰,S(O)₂R¹¹, S(O)₂NR¹⁰R¹⁰, S(O)₂NR¹⁰R¹¹, NR¹⁰S(O)₂NR¹⁰R¹¹, NR¹⁰S(O)₂R¹⁰ orNR¹⁰S(O)₂R¹¹, provided that (1) one substituent is C(O)R¹⁰, COOR¹⁰,C(O)R¹¹, COOR¹¹, C(O)NR¹⁰R¹⁰, C(S)NR¹⁰R¹⁰, C(O)NR¹⁰R¹¹, C(S)NR¹⁰R¹¹,NR¹⁰C(O)R¹⁰, NR¹⁰C(S)R¹⁰, NR¹⁰C(O)R¹¹, NR¹⁰C(S)R¹¹, NR¹⁰C(O)NR¹⁰R¹⁰,NR¹⁰C(O)NR¹⁰R¹¹, NR¹⁰(COOR¹⁰), NR¹⁰(COOR¹¹), NR¹⁰C(S)NR¹⁰R¹⁰,NR¹⁰C(S)NR¹⁰R¹¹, S(O)₂NR¹⁰R¹⁰, S(O)₂NR¹⁰R¹¹, NR¹⁰S(O)₂NR¹⁰R¹¹,NR¹⁰S(O)₂R¹⁰ or NR¹⁰S(O)₂R¹¹, in conjunction with any of the above orbelow embodiments.

For example, in the embodiment immediately above, R² may be aquinolinyl, isoquinolinyl, quinazolinyl, isoquinazolinyl, phthalazinyl,aza-phthalazinyl, benzothiophenyl, benzofuryl, benzopyrazolyl,benzotriazolyl, benzothiazolyl, benzothiadiazolyl, benzoxazolyl,benzisoxazolyl, benzoxadiazolyl, benzisothiazolyl, indolyl, isoindolyl,dihydrobenzofuranyl or benzimidazolyl ring system.

In another embodiment, the compounds are generally defined by FormulaIII

wherein

D is

wherein m is 0, 1, 2 or 3;

E is CR⁴ or N;

R² is

wherein

-   -   one of A⁶ and A⁷ is CR^(3a) and the other of A⁶ and A⁷ is        CR^(3b) or N;    -   each of A⁵, A⁸, A⁹, A¹⁰ and A¹¹ is, independently, CR^(3b) or N;    -   X² is CR^(3a);    -   each of X¹, X³ and X⁴ is, independently, CR^(3b) or N;    -   Y¹ is CR^(3b)R^(3c), NR^(3c), O or S;    -   Y² is CR^(3a)R^(3b) or NR^(3a); and    -   Z is CH or N;    -   R^(3a) is C(O)OC₁₋₃-alkylR¹¹, OC(O)R¹¹, COOR¹¹,        C(O)SC₁₋₃-alkylR¹¹, C(O)SR¹¹, C(O)N(R¹⁰)C₁₋₃-alkylR¹¹,        C(S)N(R¹⁰)C₁₋₃-alkylR¹¹, C(O)NR¹⁰R¹¹, C(S)NR¹⁰R¹¹,        NR¹⁰C(O)C₁₋₃-alkylR¹¹, NR¹⁰C(S)C₁₋₃-alkylR¹¹, NR¹⁰C(O)R¹¹,        NR¹⁰C(S)R¹¹, NR¹⁰C(O)N(R¹⁰)C₁₋₃-alkylR¹¹, NR¹⁰C(O)NR¹⁰R¹¹,        NR¹⁰C(S)N(R¹⁰)C₁₋₃-alkylR¹¹, NR¹⁰C(S)NR¹⁰R¹¹,        NR¹⁰C(O)OC₁₋₃-alkylR¹¹, NR¹⁰(COOR¹¹), OC(O)NR¹⁰R¹¹,        S(O)₂N(R¹⁰)C₁₋₃-alkylR¹¹, S(O)₂NR¹⁰R¹¹, NR¹⁰S(O)₂NR¹⁰R¹¹,        NR¹⁰S(O)₂C₁₋₃-alkylR¹¹ or NR¹⁰S(O)₂R¹¹;    -   R^(3b) is H, halo, haloalkyl, CN, NO₂, NH₂, C₁₋₁₀-alkyl,        C₂₋₁₀-alkenyl, C₂₋₁₀-alkynyl or C₃₋₁₀-cycloalkyl; and    -   R^(3c) is H, CN or C₁₋₁₀-alkyl;

R⁴ is H, halo, haloalkyl, NO₂, CN, OH, O—C₁₋₁₀-alkyl, NH₂, C₁₋₁₀-alkyl,C₂₋₁₀-alkenyl, C₂₋₁₀-alkynyl or C₃₋₁₀-cycloalkyl;

R⁵ is H, halo, haloalkyl, NO₂, CN, OH, NH₂, O—C₁₋₁₀-alkyl, C₁₋₁₀-alkyl,C₂₋₁₀-alkenyl, C₂₋₁₀-alkynyl or C₃₋₁₀-cycloalkyl;

Each R⁷, independently, is H, R⁸, C₁₋₁₀-alkyl, C₂₋₁₀-alkenyl orC₂₋₁₀-alkynyl, each of which is optionally substituted with 1-3substituents of NR⁸R⁹, NR⁹R⁹, OR⁸, SR⁸, OR⁹, SR⁹, C(O)R⁸, C(O)R⁹,C(O)NR⁸R⁹, C(O)NR⁹R⁹, S(O)₂R⁸, S(O)₂NR⁸R⁹, S(O)₂R⁹, S(O)₂NR⁹R⁹, R⁸ orR⁹;

R⁸ is a ring system selected from phenyl, pyridyl, piperazinyl,thiophenyl, furyl, pyrrolyl, imidazolyl, triazolyl, thiazolyl, oxazolyl,isoxazolyl, isothiazolyl, pyrrolidinyl, oxazolinyl, isoxazolinyl,thiazolinyl, pyrazolinyl, morpholinyl, piperidinyl, pyranyl, dioxozinyl,cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl, saidring system optionally substituted independently with 1-3 substituentsof R⁹, oxo, NR⁹R⁹, OR⁹; SR⁹ or C(O)R⁹;

R⁹ is H, halo, haloalkyl, CN, OH, NO₂, NH₂, acetyl, C₁₋₁₀-alkyl,C₂₋₁₀-alkenyl, C₂₋₁₀-alkynyl, C₃₋₁₀-cycloalkyl, C₄₋₁₀-cycloalkenyl,C₁₋₁₀-alkylamino-, C₁₋₁₀-dialkylamino-, C₁₋₁₀alkoxyl, C₁₋₁₀-thioalkoxylor a ring system selected from phenyl, naphthyl, pyridyl, piperazinyl,triazinyl, quinolinyl, isoquinolinyl, quinazolinyl, isoquinazolinyl,thiophenyl, furyl, pyrrolyl, imidazolyl, triazolyl, thiazolyl, oxazolyl,isoxazolyl, isothiazolyl, indolyl, isoindolyl, benzofuranyl,benzothiophenyl, benzimidazolyl, tetrahydrofuranyl, pyrrolidinyl,oxazolinyl, isoxazolinyl, thiazolinyl, pyrazolinyl, morpholinyl,piperidinyl, piperazinyl, pyranyl, dioxozinyl, cyclopropyl, cyclobutyl,cyclopentyl, cyclohexyl and cycloheptyl, each of the C₁₋₁₀-alkyl,C₂₋₁₀-alkenyl, C₂₋₁₀-alkynyl, C₃₋₁₀-cycloalkyl, C₄₋₁₀-cycloalkenyl,C₁₋₁₀-alkylamino-, C₁₋₁₀-dialkylamino-, C₁₋₁₀-alkoxyl, C₁₋₁₀-thioalkoxyland ring system optionally substituted independently with 1-3substituents of halo, haloalkyl, CN, NO₂, NH₂, OH, oxo, methyl,methoxyl, ethyl, ethoxyl, propyl, propoxyl, isopropyl, cyclopropyl,butyl, isobutyl, tert-butyl, methylamino, dimethylamino, ethylamino,diethylamino, propylamine, isopropylamine, dipropylamine,diisopropylamine, benzyl or phenyl;

R¹⁰ is H, CN, NO₂, C₁₋₁₀-alkyl, C₂₋₁₀-alkenyl, C₂₋₁₀-alkynyl,C₃₋₁₀-cycloalkyl or C₄₋₁₀-cycloalkenyl, each of the C₁₋₁₀-alkyl,C₂₋₁₀-alkenyl, C₂₋₁₀-alkynyl, C₃₋₁₀-cycloalkyl and C₄₋₁₀-cycloalkenyloptionally comprising 1-4 heteroatoms selected from N, O and S andoptionally substituted with one or more substituents of R¹¹, R¹² or R¹⁶,NR¹¹R¹², NR¹²R¹², OR¹¹, SR¹¹, OR¹², SR¹², C(O)R¹¹, OC(O)R¹¹, COOR¹¹,C(O)R¹², OC(O)R¹², COOR¹², C(O)NR¹¹R¹², NR¹²C(O)R¹¹, C(O)NR¹²R¹²,NR¹²C(O)R¹², NR¹²C(O)NR¹¹R¹², NR¹²C(O)NR¹²R¹², NR¹²(COOR¹¹),NR¹²(COOR¹²), OC(O)NR¹¹R¹², OC(O)NR¹²R¹², S(O)₂R¹¹, S(O)₂R¹²,S(O)₂NR¹¹R¹², S(O)₂NR¹²R¹², NR¹²S(O)₂NR¹¹R¹², NR¹²S(O)₂NR¹²R¹²,NR¹²S(O)₂R¹¹, NR¹²S(O)₂R¹², NR¹²S(O)₂R¹¹ or NR¹²S(O)R¹²;

R¹¹ is a phenyl, naphthyl, 5,6,7,8-tetrahydronaphthyl, dihydro-indenyl,pyridyl, pyrimidinyl, triazinyl, quinolinyl, tetrahydroquinolinyl,oxo-tetrahydroquinolinyl, isoquinolinyl, oxo-tetrahydroisoquinolinyl,tetrahydroisoquinolinyl, quinazolinyl, isoquinazolinyl, thiophenyl,furyl, tetrahydrofuranyl, pyrrolyl, pyrazolyl, thieno-pyrazolyl,tetrahydropentapyrazolyl, imidazolyl, triazolyl, tetrazolyl, thiazolyl,thiadiazolyl, benzothiazolyl, oxazolyl, oxadiazolyl, benzoxazolyl,benzoxadiazolyl, isoxazolyl, isothiazolyl, indolyl, azaindolyl,2,3-dihydroindolyl, isoindolyl, indazolyl, benzofuranyl,benzothiophenyl, benzimidazolyl, imidazopyridinyl, purinyl,benzotriazolyl, oxazolinyl, isoxazolinyl, thiazolinyl, pyrrolidinyl,pyrazolinyl, morpholinyl, piperidinyl, piperazinyl, pyranyl, dioxozinyl,2,3-dihydro-1,4-benzoxazinyl, 1,3-benzodioxolyl, cyclopropyl,cyclobutyl, azetidinyl, cyclopentyl, cyclohexyl or cycloheptyl ringsystem, said ring system optionally substituted independently with 1-3substituents of R¹², R¹³, R¹⁴ or R¹⁶;

alternatively, R¹⁰ and R¹¹ taken together form a partially or fullysaturated or unsaturated 5-6 membered ring of carbon atoms optionallyincluding 1-3 heteroatoms selected from O, N, or S, and the ringoptionally substituted independently with 1-3 substituents of R¹², R¹³,R¹⁴ or R¹⁶;

R¹² is H, C₁₋₁₀-alkyl, C₂₋₁₀-alkenyl, C₂₋₁₀-alkynyl, C₃₋₁₀-cycloalkyl,C₄₋₁₀-cycloalkenyl, C₁₋₁₀-alkylamino-, C₁₋₁₀-dialkylamino-,C₁₋₁₀-alkoxyl or C₁₋₁₀-thioalkyl, each of which is optionallysubstituted independently with 1-3 substituents of R¹³, R¹⁴, R¹⁵ or R¹⁶;

R¹³ is NR¹⁴R¹⁵, NR¹⁵R¹⁵, OR¹⁴; SR¹⁴, OR¹⁵; SR¹⁵, C(O)R¹⁴, OC(O)R¹⁴,COOR¹⁴, C(O)R¹⁵, OC(O)R¹⁵, COOR¹⁵, C(O)NR¹⁴R¹⁵, C(O)NR¹⁵R¹⁵,NR¹⁴C(O)R¹⁴, NR¹⁵C(O)R¹⁴, NR¹⁴C(O)R¹⁵, NR¹⁵C(O)R¹⁵, NR¹⁵C(O)NR¹⁴R¹⁵,NR¹⁵C(O)NR¹⁵R¹⁵, NR¹⁵(COOR¹⁴), NR¹⁵(COOR¹⁵), OC(O)NR¹⁴R¹⁵, OC(O)NR¹⁵R¹⁵,S(O)₂R¹⁴, S(O)₂R¹⁵, S(O)₂NR¹⁴R¹⁵, S(O)₂NR¹⁵R¹⁵, NR¹⁴S(O)₂NR¹⁴R¹⁵,NR¹⁵S(O)₂NR¹⁵R¹⁵, NR¹⁴S(O)₂R¹⁴ or NR¹⁵S(O)₂R¹⁵;

R¹⁴ is phenyl, pyridyl, pyrimidinyl, thiophenyl, furyl, tetrahydrofuryl,pyrrolyl, pyrazolyl, thieno-pyrazolyl, imidazolyl, triazolyl, thiazolyl,thiadiazolyl, benzothiazolyl, oxazolyl, oxadiazolyl, benzoxazolyl,benzoxadiazolyl, isoxazolyl, isothiazolyl, indolyl, azaindolyl,isoindolyl, indazolyl, benzofuranyl, benzothiophenyl, benzimidazolyl,pyrrolidinyl, pyrazolinyl, morpholinyl, piperidinyl, piperazinyl,2,3-dihydro-1,4-benzoxazinyl, 1,3-benzodioxolyl, cyclopropyl,cyclobutyl, azetidinyl, cyclopentyl and cyclohexyl, each of which isoptionally substituted independently with 1-3 substituents of R¹⁵ orR¹⁶;

R¹⁵ is H or C₁₋₁₀-alkyl, C₂₋₁₀-alkenyl, C₂₋₁₀-alkynyl, C₃₋₁₀-cycloalkyl,C₄₋₁₀-cycloalkenyl, C₁₋₁₀-alkylamino-, C₁₋₁₀-dialkylamino-,C₁₋₁₀-alkoxyl or C₁₋₁₀-thioalkoxyl, each of which is optionallysubstituted independently with 1-3 substituents of R¹⁶; and

R¹⁶ is H, halo, haloalkyl, CN, OH, NO₂, NH₂, OH, methyl, methoxyl,ethyl, ethoxyl, propyl, propoxyl, isopropyl, cyclopropyl, butyl,isobutyl, tert-butyl, methylamino, dimethylamino, ethylamino,diethylamino, isopropylamino, oxo, acetyl, benzyl, phenyl, cyclopropyl,cyclobutyl or a partially or fully saturated or unsaturated 5-8 memberedmonocyclic or 6-12 membered bicyclic ring system, said ring systemformed of carbon atoms optionally including 1-3 heteroatoms ifmonocyclic or 1-6 heteroatoms if bicyclic, said heteroatoms selectedfrom O, N, or S, and optionally substituted independently with 1-5substituents of halo, haloalkyl, CN, NO₂, NH₂, OH, methyl, methoxyl,ethyl, ethoxyl, propyl, propoxyl, isopropyl, cyclopropyl, butyl,isobutyl, tert-butyl, methylamino, dimethylamino, ethylamino,diethylamino, isopropylamino, benzyl or phenyl.

In other embodiments, Formulas I, II and III include various of theexemplary compounds described in the Experimentals Methods sectionhereinbelow.

Definitions

The following definitions should assist in understanding the inventiondescribed herein.

The terms “agonist” and “agonistic” when used herein refer to ordescribe a molecule which is capable of, directly or indirectly,substantially inducing, promoting or enhancing biological activity of abiological molecule, such as an enzyme or receptor, including Tie-2 andLck.

The term “comprising” is meant to be open ended, including the indicatedcomponent(s), but not excluding other elements.

The term “H” denotes a single hydrogen atom. This radical may beattached, for example, to an oxygen atom to form a hydroxyl radical.

The term “C_(α-β)alkyl”, when used either alone or within other termssuch as “haloalkyl” and “alkylamino”, embraces linear or branchedradicals having α to β number of carbon atoms (such as C₁-C₁₀).

The term “alkyl” radicals include “lower alkyl” radicals having one toabout six carbon atoms. Examples of such radicals include methyl, ethyl,n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl,isoamyl, hexyl and the like. The term “alkylenyl” embraces bridgingdivalent alkyl radicals such as methylenyl and ethylenyl.

The term “alkenyl”, when used alone or in combination, embraces linearor branched radicals having at least one carbon-carbon double bond in amoiety having between two and ten carbon atoms. Included within alkenylradicals are “lower alkenyl” radicals having two to about six carbonatoms and, for example, those radicals having two to about four carbonatoms. Examples of alkenyl radicals include, without limitation,ethenyl, propenyl, allyl, propenyl, butenyl and 4-methylbutenyl. Theterms “alkenyl” and “lower alkenyl”, embrace radicals having “cis” and“trans” orientations, or alternatively, “E” and “Z” orientations, asappreciated by those of ordinary skill in the art.

The term “alkynyl”, when used alone or in combination, denotes linear orbranched radicals having at least one carbon-carbon triple bond andhaving two to ten carbon atoms. Examples of alkynyl radicals include“lower alkynyl” radicals having two to about six carbon atoms and, forexample, lower alkynyl radicals having two to about four carbon atoms.Examples of such radicals include, without limitation, ethynyl, propynyl(propargyl), butynyl, and the like.

The term “alkoxy” or “alkoxyl”, when used alone or in combination,embraces linear or branched oxygen-containing radicals each having alkylportions of one or more carbon atoms. The term alkoxy radicals include“lower alkoxy” radicals having one to six carbon atoms. Examples of suchradicals include methoxy, ethoxy, propoxy, butoxy and tert-butoxy.Alkoxy radicals may be further substituted with one or more halo atoms,such as fluoro, chloro or bromo, to provide “haloalkoxy” radicals.Examples of such radicals include fluoromethoxy, chloromethoxy,trifluoromethoxy, trifluoroethoxy, fluoroethoxy and fluoropropoxy.

The term “aryl”, when used alone or in combination, means a carbocyclicaromatic moiety containing one, two or even three rings wherein suchrings may be attached together in a fused manner. Every ring of an“aryl” ring-system need not be aromatic, and the ring(s) fused to thearomatic ring may be partially or fully unsaturated and include one ormore heteroatoms selected from nitrogen, oxygen and sulfur. Thus, theterm “aryl” embraces aromatic radicals such as phenyl, naphthyl,indenyl, tetrahydronaphthyl, dihydrobenzafuranyl, anthracenyl, indanyl,benzodioxazinyl, and the like. The “aryl” group may be subsitituted,such as with 1 to 5 substituents including lower alkyl, hydroxyl, halo,haloalkyl, nitro, cyano, alkoxy and lower alkylamino, and the like.Phenyl substituted with —O—CH₂—O— or —O—CH₂—CH₂—O— forms an arylbenzodioxolyl substituent.

The term “carbocyclic”, also referred to herein as “cycloalkyl”, whenused alone or in combination, means a partially or fully saturated ringmoiety containing one (“monocyclic”), two (“bicyclic”) or even three(“tricyclic”) rings wherein such rings may be attached together in afused manner and formed from carbon atoms. Examples of saturatedcarbocyclic radicals include saturated 3 to 6-membered monocyclic groupssuch as cyclopropane, cyclobutane, cyclopentane and cyclohexane.

The term “cycloalkenyl”, when used alone or in combination, means apartially or fully saturated cycloalkyl containing one, two or eventhree rings in a structure having at least one carbon-carbon double bondin the structure. Examples of cycloalkenyl groups include C₃-C₆ rings,such as compounds including, without limitation, cyclopropene,cyclobutene, cyclopentene and cyclohexene. The term also includescarbocyclic groups having two or more carbon-carbon double bonds such as“cycloalkyldienyl” compounds. Examples of cycloalkyldienyl groupsinclude, without limitation, cyclopentadiene and cycloheptadiene.

The term “halo”, when used alone or in combination, means halogens suchas fluorine, chlorine, bromine or iodine atoms.

The term “haloalkyl”, when used alone or in combination, embracesradicals wherein any one or more of the alkyl carbon atoms issubstituted with halo as defined above. For example, this term includesmonohaloalkyl, dihaloalkyl and polyhaloalkyl radicals such as aperhaloalkyl. A monohaloalkyl radical, for example, may have either aniodo, bromo, chloro or fluoro atom within the radical. Dihalo andpolyhaloalkyl radicals may have two or more of the same halo atoms or acombination of different halo radicals. “Lower haloalkyl” embracesradicals having 1-6 carbon atoms and, for example, lower haloalkylradicals having one to three carbon atoms. Examples of haloalkylradicals include fluoromethyl, difluoromethyl, trifluoromethyl,chloromethyl, dichloromethyl, trichloromethyl, pentafluoroethyl,heptafluoropropyl, difluorochloromethyl, dichlorofluoromethyl,difluoroethyl, difluoropropyl, dichloroethyl and dichloropropyl.“Perfluoroalkyl”, as used herein, refers to alkyl radicals having allhydrogen atoms replaced with fluoro atoms. Examples includetrifluoromethyl and pentafluoroethyl.

The term “ring system” refers generally to a moiety comprising one ormore rings collectively having the delineated number of atoms, the atomsbeing carbon or, where indicated, a heteroatom such as nitrogen, oxygenor sulfur. The ring itself, as well as any substitutents thereon, may beattached at any atom that allows a stable compound to be formed. Theterm “nonaromatic” ring or ring system refers to the fact that at leastone, but not necessarily all, rings in a bicyclic or tricyclic ringsystem is nonaromatic.

The term “heteroaryl”, as used herein, either alone or in combination,means a fully unsaturated (aromatic) ring moiety formed from carbonatoms and having one or more heteroatoms selected from nitrogen, oxygenand sulfur. The ring moiety or ring system may contain one(“monocyclic”), two (“bicyclic”) or even three (“tricyclic”) ringswherein such rings are attached together in a fused manner. Every ringof a “heteroaryl” ring system need not be aromatic, and the ring(s)fused thereto (to the heteroaromatic ring) may be partially or fullysaturated and optionally include one or more heteroatoms selected fromnitrogen, oxygen and sulfur. The term “heteroaryl” does not includerings having ring members of —O—O—, —O—S— or —S—S—.

Examples of unsaturated heteroaryl radicals, include unsaturated 5- to6-membered heteromonocyclyl groups containing 1 to 4 nitrogen atoms,including for example, pyrrolyl, imidazolyl, pyrazolyl, 2-pyridyl,3-pyridyl, 4-pyridyl, pyrimidyl, pyrazinyl, pyridazinyl, triazolyl[e.g., 4H-1,2,4-triazolyl, 1H-1,2,3-triazolyl, 2H-1,2,3-triazolyl] andtetrazole; unsaturated 7- to 10-membered heterobicyclyl groupscontaining 1 to 4 nitrogen atoms, including for example, quinolinyl,isoquinolinyl, quinazolinyl, isoquinazolinyl, aza-quinazolinyl, and thelike; unsaturated 5- to 6-membered heteromonocyclic group containing anoxygen atom, for example, pyranyl, 2-furyl, 3-furyl, benzofuryl, etc.;unsaturated 5 to 6-membered heteromonocyclic group containing a sulfuratom, for example, 2-thienyl, 3-thienyl, benzothienyl, etc.; unsaturated5- to 6-membered heteromonocyclic group containing 1 to 2 oxygen atomsand 1 to 3 nitrogen atoms, for example, oxazolyl, isoxazolyl,oxadiazolyl [e.g., 1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl,1,2,5-oxadiazolyl]; unsaturated 5 to 6-membered heteromonocyclic groupcontaining 1 to 2 sulfur atoms and 1 to 3 nitrogen atoms, for example,thiazolyl, isothiazolyl, thiadiazolyl [e.g., 1,2,4-thiadiazolyl,1,3,4-thiadiazolyl, 1,2,5-thiadiazolyl].

The term “heterocyclic”, when used alone or in combination, means apartially or fully saturated ring moiety containing one, two or eventhree rings wherein such rings may be attached together in a fusedmanner, formed from carbon atoms and including one or more heteroatomsselected from N, O or S. Examples of saturated heterocyclic radicalsinclude saturated 3 to 6-membered heteromonocyclic groups containing 1to 4 nitrogen atoms [e.g. pyrrolidinyl, imidazolidinyl, piperidinyl,pyrrolinyl, piperazinyl]; saturated 3 to 6-membered heteromonocyclicgroup containing 1 to 2 oxygen atoms and 1 to 3 nitrogen atoms [e.g.morpholinyl]; saturated 3 to 6-membered heteromonocyclic groupcontaining 1 to 2 sulfur atoms and 1 to 3 nitrogen atoms [e.g.,thiazolidinyl]. Examples of partially saturated heterocyclyl radicalsinclude dihydrothienyl, dihydropyranyl, dihydrofuryl anddihydrothiazolyl.

The term “heterocycle” also embraces radicals where heterocyclicradicals are fused/condensed with aryl or heteroaryl radicals:unsaturated condensed heterocyclic group containing 1 to 5 nitrogenatoms, for example, indolyl, isoindolyl, indolizinyl, benzimidazolyl,quinolyl, isoquinolyl, indazolyl, benzotriazolyl, tetrazolopyridazinyl[e.g., tetrazolo[1,5-b]pyridazinyl]; unsaturated condensed heterocyclicgroup containing 1 to 2 oxygen atoms and 1 to 3 nitrogen atoms [e.g.benzoxazolyl, benzoxadiazolyl]; unsaturated condensed heterocyclic groupcontaining 1 to 2 sulfur atoms and 1 to 3 nitrogen atoms [e.g.,benzothiazolyl, benzothiadiazolyl]; and saturated, partially unsaturatedand unsaturated condensed heterocyclic group containing 1 to 2 oxygen orsulfur atoms [e.g. benzofuryl, benzothienyl,2,3-dihydro-benzo[1,4]dioxinyl and dihydrobenzofuryl]. Examples ofheterocyclic radicals include five to ten membered fused or unfusedradicals.

Examples of partially saturated and saturated heterocyclyl include,without limitation, pyrrolidinyl, imidazolidinyl, piperidinyl,pyrrolinyl, pyrazolidinyl, piperazinyl, morpholinyl, tetrahydropyranyl,thiazolidinyl, dihydrothienyl, 2,3-dihydro-benzo[1,4]dioxanyl,indolinyl, isoindolinyl, dihydrobenzothienyl, dihydrobenzofuryl,isochromanyl, chromanyl, 1,2-dihydroquinolyl,1,2,3,4-tetrahydro-isoquinolyl, 1,2,3,4-tetrahydro-quinolyl,2,3,4,4a,9,9a-hexahydro-1H-3-aza-fluorenyl,5,6,7-trihydro-1,2,4-triazolo[3,4-a]isoquinolyl,3,4-dihydro-2H-benzo[1,4]oxazinyl, benzo[1,4]dioxanyl,2,3-dihydro-1H-1λ′-benzo[d]isothiazol-6-yl, dihydropyranyl, dihydrofuryland dihydrothiazolyl, and the like.

The term “alkylamino” includes “N-alkylamino” where amino radicals areindependently substituted with one alkyl radical. Preferred alkylaminoradicals are “lower alkylamino” radicals having one to six carbon atoms.Even more preferred are lower alkylamino radicals having one to threecarbon atoms. Examples of such lower alkylamino radicals includeN-methylamino, and N-ethylamino, N-propylamino, N-isopropylamino and thelike.

The term “dialkylamino” includes “N,N-dialkylamino” where amino radicalsare independently substituted with two alkyl radicals. Preferredalkylamino radicals are “lower alkylamino” radicals having one to sixcarbon atoms. Even more preferred are lower alkylamino radicals havingone to three carbon atoms. Examples of such lower alkylamino radicalsinclude N,N-dimethylamino, N,N-diethylamino, and the like.

The terms “carboxy” or “carboxyl”, whether used alone or with otherterms, such as “carboxyalkyl”, denotes —CO₂H.

The term “carbonyl”, whether used alone or with other terms, such as“aminocarbonyl”, denotes —(C═O)—.

The term “aminocarbonyl” denotes an amide group of the formula—C(═O)NH₂.

The term “alkylthio” embraces radicals containing a linear or branchedalkyl radical, of one to ten-carbon atoms, attached to a divalent sulfuratom. An example of “alkylthio”, is methylthio, (CH₃S—).

The term “haloalkylthio” embraces radicals containing a haloalkylradical, of one to ten carbon atoms, attached to a divalent sulfur atom.An example of “haloalkylthio” is trifluoromethylthio.

The term “aminoalkyl” embraces linear or branched alkyl radicals havingone to about ten carbon atoms any one of which may be substituted withone or more amino radicals. Examples of aminoalkyl radicals include“lower aminoalkyl” radicals having one to six carbon atoms and one ormore amino radicals. Examples of such radicals include aminomethyl,aminoethyl, aminopropyl, aminobutyl and aminohexyl. Even more preferredare lower aminoalkyl radicals having one to three carbon atoms.

The term “alkylaminoalkyl” embraces alkyl radicals substituted withalkylamino radicals. Examples of alkylaminoalkyl radicals include “loweralkylaminoalkyl” radicals having alkyl radicals of one to six carbonatoms. Suitable alkylaminoalkyl radicals may be mono or dialkylsubstituted, such as N-methylaminomethyl, N,N-dimethylaminoethyl,N,N-diethylaminomethyl and the like.

The term “alkylaminoalkoxy” embraces alkoxy radicals substituted withalkylamino radicals. Examples of alkylaminoalkoxy radicals include“lower alkylaminoalkoxy” radicals having alkoxy radicals of one to sixcarbon atoms. Suitable alkylaminoalkoxy radicals may be mono or dialkylsubstituted, such as N-methylaminoethoxy, N,N-dimethylaminoethoxy,N,N-diethylaminoethoxy and the like.

The term “Formula I” includes any sub formulas, such as Formula II.Similarly, the terms “Formula II” and “Formula III” include any subformulas.

The term “pharmaceutically-acceptable” when used with reference to acompound of Formulas I-III is intended to refer to a form of thecompound that is safe for administration. For example, a salt form, asolvate, a hydrate or derivative form of a compound of Formula I, II orIII, which has been approved for mammalian use, via oral ingestion orother routes of administration, by a governing body or regulatoryagency, such as the Food and Drug Administration (FDA) of the UnitedStates, is pharmaceutically acceptable.

Included in the compounds of Formulas I-III are the pharmaceuticallyacceptable salt forms of the free-base compounds. The term“pharmaceutically-acceptable salts” embraces salts commonly used to formalkali metal salts and to form addition salts of free acids or freebases. As appreciated by those of ordinary skill in the art, salts maybe formed from ionic associations, charge-charge interactions, covalentbonding, complexation, coordination, etc. The nature of the salt is notcritical, provided that it is pharmaceutically acceptable.

Suitable pharmaceutically acceptable acid addition salts of compounds ofFormulas I-III may be prepared from an inorganic acid or from an organicacid. Examples of such inorganic acids are hydrochloric, hydrobromic,hydroiodic, hydrofluoric, nitric, carbonic, sulfuric and phosphoricacid. Appropriate organic acids may be selected from aliphatic,cycloaliphatic, aromatic, arylaliphatic, heterocyclic, carboxylic andsulfonic classes of organic acids, examples of which include, withoutlimitation, formic, acetic, adipic, butyric, propionic, succinic,glycolic, gluconic, lactic, malic, tartaric, citric, ascorbic,glucuronic, maleic, fumaric, pyruvic, aspartic, glutamic, benzoic,anthranilic, mesylic, 4-hydroxybenzoic, phenylacetic, mandelic, embonic(pamoic), methanesulfonic, ethanesulfonic, ethanedisulfonic,benzenesulfonic, pantothenic, 2-hydroxyethanesulfonic, toluenesulfonic,sulfanilic, cyclohexylaminosulfonic, camphoric, camphorsulfonic,digluconic, cyclopentanepropionic, dodecylsulfonic, glucoheptanoic,glycerophosphonic, heptanoic, hexanoic, 2-hydroxy-ethanesulfonic,nicotinic, 2-naphthalenesulfonic, oxalic, palmoic, pectinic,persulfuric, 2-phenylpropionic, picric, pivalic propionic, succinic,thiocyanic, undecanoic, stearic, algenic, β-hydroxybutyric, salicylic,galactaric and galacturonic acid. Suitable pharmaceutically-acceptablebase addition salts of compounds of Formulas I-III include metallicsalts, such as salts made from aluminum, calcium, lithium, magnesium,potassium, sodium and zinc, or salts made from organic bases including,without limitation, primary, secondary and tertiary amines, substitutedamines including cyclic amines, such as caffeine, arginine,diethylamine, N-ethyl piperidine, histidine, glucamine, isopropylamine,lysine, morpholine, N-ethyl morpholine, piperazine, piperidine,triethylamine, disopropylethylamine and trimethylamine. All of thesesalts may be prepared by conventional means from the correspondingcompound of the invention by reacting, for example, the appropriate acidor base with the compound of Formulas I, II or III.

Also, the basic nitrogen-containing groups can be quaternized with suchagents as lower alkyl halides, such as methyl, ethyl, propyl, and butylchloride, bromides and iodides; dialkyl sulfates like dimethyl, diethyl,dibutyl, and diamyl sulfates, long chain halides such as decyl, lauryl,myristyl and stearyl chlorides, bromides and iodides, aralkyl halideslike benzyl and phenethyl bromides, and others. Water or oil-soluble ordispersible products are thereby obtained.

Examples of acids that may be employed to form pharmaceuticallyacceptable acid addition salts include such inorganic acids ashydrochloric acid, hydrobromic acid, citric acid, sulphuric acid andphosphoric acid and such organic acids as oxalic acid, stearic and,salicylic acid, pamoic acid, gluconic acid, ethanesulfonic acid,methanesulfonic acid, toluenesulfonic acid, tartaric acid, fumaric acid,medronic acid, napsylic acid, maleic acid, succinic acid and citricacid. Other examples include salts with alkali metals or alkaline earthmetals such as sodium, potassium, calcium or magnesium, or with organicbases.

Additional examples of such salts can be found in Berge et al., J.Pharm. Sci., 66, 1 (1977). Conventional methods may be used to form thesalts. For example, a phosphate salt of a compound of the invention maybe made by combining the desired compound free base in a desiredsolvent, or combination of solvents, with phosphoric acid in a desiredstoichiometric amount, at a desired temperature, typically under heat(depending upon the boiling-point of the solvent). The salt can beprecipitated upon cooling (slow or fast) and may crystallize (i.e., ifcrystalline in nature), as appreciated by those of ordinary skill in theart. Further, hemi-, mono-, di, tri- and poly-salt forms of thecompounds of the present invention are also contemplated herein.Similarly, hemi-, mono-, di, tri- and poly-hydrated forms of thecompounds, salts and derivatives thereof, are also contemplated herein.

The term “derivative” is broadly construed herein, and intended toencompass any salt of a compound of this invention, any ester of acompound of this invention, or any other compound, which uponadministration to a patient is capable of providing (directly orindirectly) a compound of this invention, or a metabolite or residuethereof, characterized by the ability to the ability to modulate akinase enzyme.

The term “pharmaceutically-acceptable derivative” as used herein,denotes a derivative which is pharmaceutically acceptable.

The term “prodrug”, as used herein, denotes a compound which uponadministration to a subject or patient is capable of providing (directlyor indirectly) a compound of this invention. Examples of prodrugs wouldinclude esterified or hydroxylated compounds where the ester or hydroxylgroups would cleave in vivo, such as in the gut, to produce a compoundaccording to Formulas I-III. A “pharmaceutically-acceptable prodrug” asused herein, denotes a prodrug which is pharmaceutically acceptable.Pharmaceutically acceptable modifications to the compounds of FormulasI-III are readily appreciated by those of ordinary skill in the art.

The compound(s) of Formula I, II or III may be used to treat a subjectby administering the compound(s) as a pharmaceutical composition. Tothis end, the compound(s) can be combined with one or more carriers,diluents or adjuvants to form a suitable composition, which is describedin more detail herein.

The term “carrier”, as used herein, denotes any pharmaceuticallyacceptable additive, excipient, adjuvant, or other suitable ingredient,other than the active pharmaceutical ingredient (API), which istypically included for formulation and/or administration purposes.“Diluent” and “adjuvant” are defined hereinafter.

The terms “treat”, “treating,” “treatment,” and “therapy” as used hereinrefer to therapy, including without limitation, curative therapy,prophylactic therapy, and preventative therapy. Prophylactic treatmentgenerally constitutes either preventing the onset of disordersaltogether or delaying the onset of a pre-clinically evident stage ofdisorders in individuals.

The phrase “effective dosage amount” is intended to quantify the amountof each agent, which will achieve the goal of improvement in disorderseverity and the frequency of incidence over treatment of each agent byitself, while avoiding adverse side effects typically associated withalternative therapies. As such, this term is not limited to a singleunit dosage, to be effective. Accordingly, it is contemplated hereinthat an “effective dosage amount” may include more than one unit dosageto be administered to the subject. For example, the subject may beprescribed, or requested by qualifie medical staff, to ingest 2 tablets,which comprise a compound of the invention, to obtain an effectivedosage amount.

The term “leaving groups” generally refer to groups that aredisplaceable by a nucleophile. Such leaving groups are known in the art.Examples of leaving groups include, but are not limited to, halides(e.g., I, Br, F, Cl), sulfonates (e.g., mesylate, tosylate), sulfides(e.g., SCH₃), N-hydroxsuccinimide, N-hydroxybenzotriazole, and the like.Nucleophiles are species that are capable of attacking a molecule at thepoint of attachment of the leaving group causing displacement of theleaving group. Nucleophiles are known in the art. Examples ofnucleophilic groups include, but are not limited to, amines, thiols,alcohols, Grignard reagents, anionic species (e.g., alkoxides, amides,carbanions) and the like.

The term “angiogenesis” is defined as any alteration of an existingvascular bed or the formation of new vasculature which benefits tissueperfusion. This includes the formation of new vessels by sprouting ofendothelial cells from existing blood vessels or the remodeling ofexisting vessels to alter size, maturity, direction and/or flowproperties to improve blood perfusion of tissue.

The terms “cancer” and “cancerous” when used herein refer to or describethe physiological condition in mammals that is typically characterizedby unregulated cell growth. Examples of cancer include, withoutlimitation, carcinoma, lymphoma, sarcoma, blastoma and leukemia. Moreparticular examples of such cancers include squamous cell carcinoma,lung cancer, pancreatic cancer, cervical cancer, bladder cancer,hepatoma, breast cancer, colon carcinoma, and head and neck cancer.While the term “cancer” as used herein is not limited to any onespecific form of the disease, it is believed that the methods of theinvention will be particularly effective for cancers which are found tobe accompanied by unregulated levels of Tie-2, and similar kinases, inthe subject.

General Synthetic Procedures

The present invention further comprises procedures for the preparationof a compound of Formulas I-III. The compounds of Formulas I-III can besynthesized according to the procedures described in the followingSchemes 1-6, wherein the substituents are generally as defined forFormulas I-III above, except where further noted. The synthetic methodsdescribed below are merely exemplary, and the compounds of the inventionmay be synthesized by alternate routes as appreciated by persons ofordinary skill in the art.

The following list of abbreviations used throughout the specificationrepresent the following and should assist in understanding theinvention:

-   ACN, MeCN—acetonitrile-   BSA—bovine serum albumin-   Cs₂CO₃—cesium carbonate-   CHCl₃—chloroform-   CH₂Cl₂, DCM—dichloromethane, methylene chloride-   CuBr—copper bromide-   CuI—copper iodide-   DIBAL—diisobutylaluminum hydride-   DIC—1,3-diisopropylcarbodiimide-   DIEA, (iPr)₂NEt—diisopropylethylamine-   DME—dimethoxyethane-   DMF—dimethylformamide-   DMAP—4-dimethylaminopyridine-   DMSO—dimethylsulfoxide-   EDC—1-(3-dimethylaminopropyl)-3-ethylcarbodiimide-   Et₂O—diethyl ether-   EtOAc—ethyl acetate-   FBS—fetal bovine serum-   G, gm—gram-   h, hr—hour-   H₂—hydrogen-   HATU—O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluroniumhexafluorophosphate-   HBr—hydrobromic acid-   HCl—hydrochloric acid-   HOBt—1-hydroxybenzotriazole hydrate-   HPLC—high pressure liquid chromatography-   IPA, IpOH—isopropyl alcohol-   K₂CO₃—potassium carbonate-   KI—potassium iodide-   MgSO₄—magnesium sulfate-   MeOH—methanol-   N₂—nitrogen-   NaCNBH₃—sodium cyanoborohydride-   NaHCO₃—sodium bicarbonate-   NaH—sodium hydride-   NaOCH₃—sodium methoxide-   NaOH—sodium hydroxide-   Na₂SO₄—sodium sulfate-   NH₄Cl—ammonium chloride-   NH₄OH—ammonium hydroxide-   NMP—N-methylpyrrolidinone-   P(t-bu)₃—tri(tert-butyl)phosphine-   PBS—phospate buffered saline-   Pd/C—palladium on carbon-   Pd(PPh₃)₄—palladium(0)triphenylphosphine tetrakis-   PdCl₂(PPh₃)₂—palladiumdichloro-diphenylphosphine-   Pd(OAc)₂—palladium acetate-   PyBop—benzotriazol-1-yl-oxy-tripyrrolidino-phosphonium    hexafluorophosphate-   RT—room temperature-   TBTU—O-benzotriazol-1-yl-N,N,N′,N′-tetramethyluronium    tetrafluoroborate-   TEA, Et₃N—triethylamine-   TFA—trifluoroacetic acid-   THF—tetrahydrofuran

A heteroaryl-substituted alkynes 5 can be prepared according to themethod generally described in Scheme 1, wherein the heteroaryl isdesignated as C, while A and B are independent ring systems,respectively, and “L” is a linker connecting ring A to ring B. As shown,a halogen-substituted B ring system 1, having a linker portion L_(b) canbe reacted with a substituted A ring system 2 having a correspondinglinker portion L_(a). Linker portions L_(a) and L_(b) are capable ofreacting with one another to form compound 3 having the desired linker“L”. “L” may be any linker generally defined by the R² substitutions inFormulas I, II and III, and particularly, it includes, withoutlimitation, an amide, a urea, a thiourea, a thioamide, a carbamate, ananhydride, a sulfonamide and the like, allowing for spacer atoms eitherbetween ring B and L and/or between ring A and L, as described in Scheme3 below. Accordingly, various desirable linker “L”s can be formed fromsuitable linker portions L_(a) and L_(b), respectively.

Halogen-B-A intermediates 3 can be coupled to suitableheteroaryl-substituted alkynes 4 using conventional metallationchemistry methods, such as those disclosed by Stephen Buchwald. Forexample, compound 3 where X=iodide can be coupled to an alkyne 4 in thepresence of palladium and copper under suitable basic solutionconditions. Generally, suitable palladium reagents include PdCl₂(PPh₃)₂,and the like. Suitable solvents include polar solvents such as ACN orDMF and suitable bases include weak tertiary amine bases such as TEA.Suitable reaction conditions may involve heating the reaction to asuitable temperature to allow complete coupling between thehalogen-intermediate 3 and alkyne 4.

Alternatively, heteroaryl-substituted alkynes 5 can be preparedaccording to the method generally described in Scheme 2. As shown anddescribed in scheme 1, a halogen-substituted B ring system-linked-A ringsystem intermediate 3 can be made. The halogen group of compound 3 canbe converted to the corresponding acetylide 6, as shown in step 2, byreaction with a suitable acetylene donor, such as a silyl acetylide,under suitable reactions conditions. Such reactions generally take placewith suitable metal catalysts, such as palladium and copper. Thereaction may proceed under ambient temperature, or may require heat,depending upon the particular intermediate 3, acetylene reagent,concentration of reagents, solvent, and other factors, as appreciated bypersons of ordinary skill in the art.

The acetylide 6 can then be reacted with a desired heteroaryl halide 7to yield the desired heteroaryl-substituted alkyne 5.

R² ring system, generally designated and referred to in Scheme 3, andthroughout the specification, as the “B” ring may be substituted withvarious substitutions including R¹¹ ring systems, generally designatedand referred to in Scheme 3, and throughout the specification, as the“A” ring system, by various coupling methods as described in Scheme 3.Each of the seven sub-schemes, numbered 1-7 above and described below,utilize the following meanings for (R)_(n), X, Nu⁻, E⁺, W and m: (R)_(n)refers to n number of R¹⁰, R¹¹ and R¹⁶ substitutions wherein n is aninteger from 0-9; X refers generally to a “leaving group” such as ahalide (bromine, chlorine, iodine or fluorine), alkylsulfonate and otherknown groups (also see definitions herein); Nu⁻ refers generally to anucleophilic species such as a primary or secondary amine, an oxygen, asulfur or a anionic carbon species—examples of nucleophiles include,without limitation, amines, hydroxides, alkoxides and the like; E⁺refers generally to an electrophilic species, such as the carbon atom ofa carbonyl, which is susceptible to nucleophilic attack or readilyeliminates—examples of suitable electrophilic carbonyl species include,without limitation, acid halides, mixed anhydrides, aldehydes,carbamoyl-chlorides, sulfonyl chlorides, acids activated with activatingreagents such as TBTU, HBTU, HATU, HOBT, BOP, PyBOP, carbodiimides (DCC,EDC and the like), pentafluorophenyl, and other electrophilic speciesincluding halides, isocyanates, daizonium ions and the like; W is eitherO or S; and m is either 0 or 1.

The coupling of rings B and A, as shown as products in sub-schemes 1-7,can be brought about using various conventional methods to link rings Band A together. For example, an amide or a sulfonamide linkage, as shownin sub-schemes 2 and 4, and 5 and 7 where the Nu− is an amine,respectively, can be made utilizing an amine on either the B or A ringsand an acid chloride or sulfonyl chloride on the other of either the Bor A rings. The reaction proceeds generally in the presence of asuitable solvent and/or base. Suitable solvents include, withoutlimitation, generally non-nucleophilic, a solvent such as toluene,CH₂Cl₂, THF, DMF, DMSO, N,N-dimethylacetamide and the like, includingsolvent combinations thereof. The solvent may range in polarity, asappreciated by those skilled in the art. Suitable bases include, forexample, tertiary amine bases such as DIEA, TEA, carbonate bases such asNa₂CO₃, K₂CO₃, Cs₂CO₃, hydrides such as NaH, KH, borohydrides,cyanoborohydrides and the like, alkoxides such as NaOCH₃, and the like.The base itself may also serve as a solvent. The reaction may optionallybe run neat, i.e., without any base and/or solvent. These couplingreactions are generally fast and conversion occurs typically in ambientconditions. However, depending upon the particular substrate,concentration and other stoichiometric factors, such reactions mayrequire heat, as appreciated by those skilled in the art.

Similarly, carbamates as illustrated in sub-scheme 1 where Nu− is anamine, anhydrides as illustrated in sub-scheme 1 where Nu− is an oxygen,reverse amides as generally illustrated in sub-scheme 6 where Nu− is anamine and E+ is an acid chloride, ureas as illustrated in sub-scheme 3,thioamides and thioureas where the respective carbonyl oxygen is asulfur, thiocarbamates where the respective carbonyl oxygen and/orcarbamate oxygen is a sulfur, and the like. While the above methods areso described, they are not exhaustive, and other methods for linkingrings A and B together may be utilized as appreciated by those skilledin the art.

Although sub-schemes 1-7 are illustrated as having the nucleophilic andelectrophilic coupling groups, such as the amino group and acid chloridegroups illustrated in sub-scheme 2, directly attached to the substrate,either the A or B ring, in question, the invention is not so limited. Itis contemplated herein that these nucleophilic and/or electrophiliccoupling groups may be tethered from their respective ring. For example,the amine group on the B ring, and/or the acid halide group on the Aring, as illustrated in sub-scheme 2, may be removed from directattachment to the ring by a one or more atom spacer, such as by amethylene, ethylene, propylene spacer or the like. As appreciated bythose skilled in the art, such spacer may or may not affect the couplingreactions described above, and accordingly, such reaction conditions mayneed to be modified to affect the desired transformation.

The coupling methods described in sub-schemes 1-7 of scheme 3 are alsoapplicable for coupling desired A rings to desired C-B intermediates, tosynthesize desired compounds of Formulas I, II and III. For example, ahalo-B-NH₂ ring may first be coupled to a heteroaryl-substituted alknyeintermediate 4 (scheme 1, also referred to as the C ring) to form theC-B intermediate. The B ring amine group of this C-B intermediate maythen be converted to an isocyanate, for example, or any other desiredgroup for coupling the A ring via the desired linker. Further, the Bring amine may be protected, such as with BOC-ON, while furthersubstituents are coupled to the B ring and/or the C ring, prior tocoupling the C-B intermediate to an A ring (see Scheme 5 below).

Various R⁷ substitutions and/or R⁸ substitutions (not shown) can beinstalled in the C ring portion, at a desired location on the C ring ofthe compounds of Formulas I, II and III, with or without the B-A ringsystem attached, as described in Scheme 4. For instance, compounds 8, 9,10 and 11 may be made by the method described in Scheme 4. As shown,amino substitutions R⁷ may be made by reacting the amino heteroarylsubstituted alkyne compound 4a with a desired R group having a leavinggroup (“LG”), suitable for reaction with an aryl NH₂. For example, amethyl group may be covalently bound to the amine via reaction withmethyl iodide. Similarly, a 2-dimethylamino substitution may be obtainedvia excess methyl iodide, or similar methylating reagent. Base may ormay nor be needed, as appreciated by those skilled in the art.Similarly, amide or sulfonamide linkers may be obtained where R⁷ (or R⁸)is an activated carbonyl or sulfonyl species, such as an acid orsulfonyl chloride and the like. The acetylene group on compound 4a mayneed to be protected such as with a silyl group or the like, to preventreaction at that site during the reaction to install the R⁷ and/or R⁸groups, and later deprotected to couple the desired C ring system to thedesired B-A ring system, utilizing methods described in Scheme 3. Suchis readily appreciated by those skilled in the art. Such protection mayor may not be necessary while functionalizing an amino group off of theC ring in compound 10, depending upon the particular substitutions onrings A and B.

Various R¹⁰, R¹¹ and R¹⁶ substitutions, as shown on compounds 3b and 12,can be installed on the B ring of Formulas I-III, with or without the Cring system attached, as described in Scheme 5. For instance, compounds3b and 12 may be made by the method described in Scheme 5. As shown,iodinated compounds 3a (X=I) and compounds 5b may contain suitableleaving groups, such as a fluoride, at a desired position on the B ringfor substitution. Intermediates 3a and 5b may be reacted with desirablenucleophilic R groups (R¹⁰, R¹¹ and R¹⁶ substitutions), such asalkoxides, amines and the like, in the presence of a suitable base, suchas a hydride or borohydride, to covalently bind the R group to the Bring. Alternatively, the B ring may have a nucleophile (not shown), suchas a hydroxide or an amine, which may be further functionalized asdesired via standard chemical methodology, as appreciated by thoseskilled in the art.

Various R¹², R¹³, R¹⁴ and R¹⁶ substitutions, as shown on compounds 3dand 13, can be installed on the A ring of Formulas I-III, with orwithout the C ring system attached, as described in Scheme 6. Forinstance, compounds 3d and 13 may be made by the method described inScheme 6. As shown, iodinated (X=I; or amino-protected, which is notshown) aryl B ring compounds 3c, and compounds 5c may contain suitableleaving groups on the A ring, such as a halide, sulfonate, activatedacid, anhydride, ester, hydroxide and the like, at a desired positionfor substitution. Intermediates 3c and 5c may be reacted with desirablenucleophilic R groups (R¹², R¹³, R¹⁴ and R¹⁶ substitutions), such asalkoxides, amines and the like, in the presence of a suitable base, suchas a tertiary amine base, carbonate or bicarbonate bases, hydride orborohydride bases, hydroxide and alkoxide bases, and stronger bases asnecessary, to covalently bind the R group to the A ring. Other R groupssuch as aryl rings, acetylene groups, and the like may be attachedutilizing Suzuki methods or other metal chemistry as appreciated by theskilled artisan. Alternatively, the A ring may have a nucleophile, suchas a hydroxide or an amine, which may be further functionalized asdesired via standard chemical methodology, as appreciated by thoseskilled in the art.

To enhance the understanding and appreciation of the present invention,the following exemplary methods and specific examples (startingreagents, intermediates and compounds of Formulas I, II and III) are setforth. It should be appreciated that these methods and examples aremerely for illustrative purposes only and are not to be construed aslimiting the scope of this invention in any manner.

Analytical Methods:

Unless otherwise indicated, all HPLC analyses were run on a AgilentModel 1100 system with an Agilent Technologies Zorbax SB-C₈(5μ) reversephase column (4.6×150 mm; Part no. 883975-906) run at 30° C. with a flowrate of about 1.50 mL/min. The mobile phase used solvent A (H₂O/0.1%TFA) and solvent B (ACN/0.1% TFA) with a 11 min gradient from 5% to 100%ACN. The gradient was followed by a 2 min. return to 5% ACN and about a2.5 min. re-equilibration (flush).

LC-MS Method:

Samples were run on an Agilent model-1100 LC-MSD system with an AgilentTechnologies XDB-C₈ (3.5μ) reverse phase column (4.6×75 mm) at 30° C.The flow rate was constant and ranged from about 0.75 mL/min to about1.0 mL/min.

The mobile phase used a mixture of solvent A (H₂O/0.1% HOAc) and solventB (ACN/0.1% HOAc) with a 9 min time period for a gradient from 10% to90% solvent B. The gradient was followed by a 0.5 min period to returnto 10% solvent B and a 2.5 min 10% solvent B re-equilibration (flush) ofthe column.

Preparative HPLC Method:

Where indicated, compounds of interest were purified via reverse phaseHPLC using a Gilson workstation utilizing one of the following twocolumns and methods:

(A) Using a 50×100 mm column (Waters, Exterra, C18, 5 microns) at 50mL/min. The mobile phase used was a mixture of solvent A (H₂O/10 mMammonium carbonate at pH about 10, adjusted with conc. NH₄OH) andsolvent B (85:15 ACN/water, 10 mM ammonium carbonate at pH of about 10adjusted with conc. NH₄OH). Each purification run utilized a 10 minutegradient from 40% to 100% solvent B followed by a 5 minute flow of 100%solvent B. The gradient was followed by a 2 min return to 40% solvent B.(B) Using a 20×50 mm column at 20 mL/min. The mobile phase used was amixture of solvent A (H₂O/0.1% TFA) and solvent B (ACN/0.1% TFA) with a10 min gradient from 5% to 100% solvent B. The gradient is followed by a2 min return to 5% ACN.Proton NMR Spectra:

Unless otherwise indicated, all ¹H NMR spectra were run on a Varianseries Mercury 300 MHz instrument or a Bruker series 400 MHz instrument.Where so characterized, all observed protons are reported asparts-per-million (ppm) downfield from tetramethylsilane (TMS) or otherinternal reference in the appropriate solvent indicated.

Mass Spectra (MS)

Unless otherwise indicated, all mass spectral data for startingmaterials, intermediates and/or exemplary compounds are reported asmass/charge (m/z), having an (M+H⁺) molecular ion. The molecular ionreported was obtained by electrospray detection method. Compounds havingan isotopic atom, such as bromine and the like, are reported accordingto the detected isotopic pattern, as appreciated by those skilled in theart.

The following examples represent various starting materials andintermediates, which should assist in better understanding andappreciating the exemplary methods of synthesizing compounds of FormulasI, II and III.

Various experimental methods have been employed to synthesize compoundsof Formulas I-III, as more generally described in schemes 1-6 above, andfurther described in more detail by the representative examples below.

Experimental Method A1

Example 1

Synthesis of3-(2-(2-aminopyrimidin-5-yl)ethynyl)-4-methyl-N-(3-(trifluoromethyl)phenyl)benzamideStep 1. Preparation of3-iodo-4-methyl-N-(3-(trifluoromethyl)phenyl)benzamide

3-Iodo-4-methylbenzoic acid (2.0 g, 7.6 mmol) was taken up in SOCl₂ (4mL). The resulting slurry was allowed to reflux for 2 h upon which timethe reaction was concentrated under reduced pressure to afford thecorresponding acid chloride, which was used without furtherpurification. The off white acid-chloride solid was taken up in CH₂Cl₂(70 mL) followed by the addition of DIEA (1.5 mL, 8.4 mmol) and3-(trifluoromethyl)aniline (0.86 mL, 6.9 mmol). The mixture was allowedto stir at room temperature for 3 h. The reaction mixture was dilutedwith CH₂Cl₂ (70 mL) and washed with aq. HCl (1M, 25 mL), sat. aq. NaHCO₃(25 mL), brine (25 mL), dried over anhydrous sodium sulfate, filteredand concentrated under reduced pressure to afford3-iodo-4-methyl-N-(3-(trifluoromethyl)phenyl)benzamide as an off whitesolid. MS m/z=406 [M+H]⁺. Calc'd for C₁₅H₁₁F₃INO: 405.

Step 2: Preparation of3-(2-(2-aminopyrimidin-5-yl)ethynyl)-4-methyl-N-(3-(trifluoromethyl)phenyl)benzamide

To a sealable tube containing 5-ethynylpyrimidin-2-amine (172 mg, 1.44mmol), PdCl₂(PPh₃)₂ (25 mg, 0.036 mmol),3-iodo-4-methyl-N-(3-(trifluoromethyl)phenyl)benzamide (292 mg, 0.72mmol) was added MeCN (10 mL) and Et₃N (3 mL) followed by CuI (6.8 mg,0.036 mmol). The tube was sealed and heated at 90° C. for 1 h. Thereaction was allowed to cool to room temperature and concentrated underreduced pressure. The resulting brown solid was reconstituted inMeOH:CH₂Cl₂ (1:1, 10 mL) and silica gel was added and reconcentrated.The silica-gel combined crude mixture was purified via automated flashchromatography (silica gel, 0 to 5% MeOH in CH₂Cl₂, gradient elution) toafford3-(2-(2-aminopyrimidin-5-yl)ethynyl)-4-methyl-N-(3-(trifluoromethyl)phenyl)benzamide.MS m/z=397 [M+H]⁺. Calc'd for C₂₁H₁₅F₃N₄O: 396

Example 2

Synthesis of3-(2-(2-aminopyrimidin-5-yl)ethynyl)-4-methyl-N-(3-((4-methylpiperazin-1-yl)methyl)-5-(trifluoromethyl)phenyl)benzamideStep 1: Preparation of3-iodo-4-methyl-N-(3-((4-methylpiperazin-1-yl)methyl)-5-(trifluoromethyl)phenyl)benzamide

To a solution of3-((4-methylpiperazin-1-yl)methyl)-5-(trifluoromethyl)-benzenamine(0.274 g, 1 mmol) in CH₂Cl₂ (3 mL) at room temperature was added3-iodo-4-methylbenzoyl chloride (0.267 g, 0.95 mmol). The mixture wasallowed to stir for 20 h. The reaction was concentrated under reducedpressure, and purified via column chromatography (0 to 20% methanol indichloromethane) to afford3-iodo-4-methyl-N-(3-((4-methylpiperazin-1-yl)methyl)-5-(trifluoromethyl)phenyl)benzamide.MS m/z=518. Calc'd for C₂₄H₁₈ClF₃N₄O: 517.33.

Step 2: Preparation of3-(2-(2-aminopyrimidin-5-yl)ethynyl)-4-methyl-N-(3-((4-methylpiperazin-1-yl)methyl)-5-(trifluoromethyl)phenyl)benzamide

Aryl iodide (0.113 g, 0.22 mmol), 2-amino-5-ethynylpyrimidine (0.53 g,0.44 mmol), Palladium dichloro-bis-triphenylphosphine (0.008 g, 0.011mmol), and copper(I) iodide were placed into a vial. Acetonitrile (10mL) and triethylamine (2 mL) were added, and the mixture was heated withstirring at 90 C for 1 hour. The misture was cooled to room temperature,concentrated under reduced pressure and adsorbed onto silica gel. Flashchromatography of the pre-absorbed mixture (eluting with 0 to 20%methanol in dichloromethane) afforded3-(2-(2-aminopyrimidin-5-yl)ethynyl)-4-methyl-N-(3-((4-methylpiperazin-1-yl)methyl)-5-(trifluoromethyl)phenyl)benzamideas a yellow semi-solid. MS m/z=509. Calc'd for C₂₄H₁₈ClF₃N₄O: 508.54.

Example 2a

Synthesis ofN-cyclopropyl-4-methyl-3-(2-(6-(2-morpholinoethylamino)pyridin-3-yl)ethynyl)benzamideStep 1: 5-iodo-N-(2-morpholinoethyl)pyridin-2-amine

2-Chloro-5-iodopyridine (2.21 g, 9.25 mmol) was dissolved in2-morpholinoethanamine (10 mL) and placed in the microwave for 30 min.at about 180° C. The reaction mixture was diluted with 100 mL EtOAc,washed with 50 mL saturated, aqueous NaHCO₃, and dried over anhydrousNa₂SO₄. After purification by chromatography, the title compound wasobtained. MS (ES+): 334 (M+H)⁺.

Step 2:N-(2-morpholinoethyl)-5-(2-(trimethylsilyl)ethynyl)pyridin-2-amine

5-Iodo-N-(2-morpholinoethyl)pyridin-2-amine (0.82 g, 2.46 mmol), TMSacetylene (1.70 mL, 12.3 mmol), and triethylamine (0.69 mL, 4.92 mmol)were dissolved in dioxane (20 mL) and with nitrogen for about 15 min.Tetrakis(triphenylphosphine)palladium (142 mg, 0.12 mmol) and copper (I)iodide (47 mg, 0.25 mmol) were added before the reaction mixture washeated to 80° C. for 3.5 h. The reaction mixture was diluted with 100 mLEtOAc, washed with 50 mL saturated, aqueous NaHCO₃, and dried overanhydrous Na₂SO₄. After purification by chromatography, the titlecompound was obtained. MS (ES+): 304 (M+H)⁺.

Step 3: 5-ethynyl-N-(2-morpholinoethyl)pyridin-2-amine

N-(2-morpholinoethyl)-5-(2-(trimethylsilyl)ethynyl)pyridin-2-amine (2.0g, 6.60 mmol) was dissolved in methanol (30 mL) before it was cooled to0° C. and potassium carbonate (1.0 g, 7.26 mmol) added. The reactionmixture was stirred for 1 h at ambient temperature, then diluted with 50mL EtOAc, washed with 20 mL saturated, aqueous NaHCO₃, and dried overanhydrous Na₂SO₄ to give the title compound. MS (ES+): 232 (M+H)⁺.

Step 4: N-cyclopropyl-3-iodo-4-methylbenzamide

To 3-iodo-4-methylbenzoic acid (3.5 g, 13 mmol) was added thionylchloride (10 mL) before heating the mixture to reflux for 1.5 h. Thereaction mixture was concentrated in vacuo, and dissolved in DCM (50 mL)and Hünigs base (4.6 mL, 27 mmol). After the addition ofcyclopropylamine (1.87 mL, 27 mmol) at −78° C., the reaction mixture wasstirred at ambient Temp. for about 3 h. The mixture was diluted with 100mL DCM, washed with 20 mL saturated, aqueous NaHCO₃ and 20 mL 3 N HCl,and dried over anhydrous Na₂SO₄. The solid obtained was suspended inEtOAc and filtered to give the title compound. MS (ES+): 302 (M+H)⁺.

Step 5:N-cyclopropyl-4-methyl-3-(2-(6-(2-morpholinoethylamino)pyridin-3-yl)ethynyl)benzamide

5-Ethynyl-N-(2-morpholinoethyl)pyridin-2-amine (0.54 g, 2.36 mmol),N-cyclopropyl-3-iodo-4-methylbenzamide (0.71 g, 2.36 mmol), andtriethylamine (0.49 mL, 3.54 mmol) were dissolved in dioxane (10 mL)before these were sparged with nitrogen for 15 min.; palladiumdichloro-bis-triphenylphosphine (83 mg, 0.12 mmol) and copper (I) iodide(45 mg, 0.24 mmol) were added before the reaction mixture was heated to90° C. for 6 h. The reaction mixture was diluted with 100 mL EtOAc,washed with 50 mL saturated, aqueous NaHCO₃, and dried over anhydrousNa₂SO₄. After purification by chromatography, the title compound wasobtained as a yellow oil. MS (ES+): 406 (M+H)⁺.

The following Examples 3-75 were prepared by a method similar to thatdescribed in Experimental Method A1 and Examples 1, 2 and 2a.

Example MS Data MS Data No. Structure Method MW M + 1 M − 1 3

A1 383.33 384 4

A1 400.33 401 5

A1 494.52 495 6

A1 510.56 511 7

A1 439.44 440 8

A1 508.55 509 9

A1 522.57 523 10

A1 508.5 509

11

A1 495.55 496 12

A1 522.57 523 13

A1 512.5 513

14

A1 514.52 515 15

A1 512.51 513 16

A1 440.54 441 17

A1 422.41 423 18

A1 436.44 437 19

A1 492.46 493 20

A1 515.51 516 21

A1 511.55 512 22

A1 477.49 478 23

A1 493.53 494 24

A1 388.37 389 25

A1 502.56 503 26

A1 384.48 385 27

A1 498.67 500 28

A1 490.67 491 29

A1 464.37 465 30

A1 416.79 417 31

A1 545.01 545 32

A1 404.9 405 33

A1 404.9 405 34

A1 524.59 525 35

A1 574.63 575 36

A1 388.37 389 37

A1 526.5 527

38

A1 477.01 477 39

A1 430.82 429 40

A1 384.48 383 41

A1 512.5 513

42

A1 512.51 513 43

A1 522.53 523 44

A1 526.49 527 45

A1 426.4 425 46

A1 558.58 559 47

A1 485.53 486 48

A1 548.97 549 49

A1 578.59 579 50

A1 562.55 563 51

A1 410.4 409 52

A1 412.37 411 53

428.37 427 54

A1 502.56 503 55

A1 502.56 503 56

A1 561.51 562 57

A1 563 563 58

A1 467.38 468 59

A1 356.43 357 60

A1 457.43 458 61

A1 333.35 332 62

A1 486.59 487 63

A1 501.53 502 64

A1 363.4 364

65

A1 349.35 348 66

A1 497.54 498 67

A1 347.38 346 68

A1 363.38 362 69

A1 509.53 508 70

A1 430.43 431 71

A1 512.51 513 72

A1 512.51 513 73

A1 494.52 493 74

A1 524.54 525 75

A1 538.57 539

The following Examples 76-77 were prepared by a method (Method A2)similar to that described in Experimental Method A1 and Example 2,utilizing a conventional acid to amine coupling reagent, such as HOBT,HATU, HBTU, pentafluorophenyl ester and the like, in step 1.

Example MS Data MS Data No. Structure Method MW M + 1 M − 1 76

A1 383.33 384 77

A1 383.33 384

Experimental Method A3

Example 77-V

N-(4-(2-(2-aminopyrimidin-5-yl)ethynyl)naphthalen-1-yl)-1H-benzo[d]imidazol-2-amineStep 1: 1-bromo-4-isothiocyanatonaphthalene

To a solution of 1-bromo-4-aminonapthalene (2.6 g, 12 mmol) indichloromethane (45 mL) was added di(1H-imidazol-1-yl)methanethione (2.1g, 12 mmol). The reaction was allowed to stir for 16 h, at which pointthe reaction was concentrated to give a gray solid. The solid wasslurried in 50% EtOAc/hexanes and filtered through a pad of silica gel,rinsing with 400 mL 50% EtOAc/hexanes. The solution was concentrated togive 1-bromo-4-isothiocyanatonaphthalene as a gray solid, which was usedwithout further purification.

Step 2: N-4-bromonaphthalen-1-yl)-1H-benzo[d]imidazol-2-amine

A slurry of 1-bromo-4-isothiocyanatonaphthalene (1.0 g, 3.8 mmol),o-phenylene diamine (0.45 g, 4.2 mmol), and polymer-supportedcarbodiimide (9.0 g, 11 mmol, 1.27 mmol/g) in 72 mL THF was heated to70° C. with a water-cooled reflux condenser for 3 h. The reaction wasfiltered, rinsing with dichloromethane. The solution was concentrated toa yellow solid, suspended in dichloromethane, and filtered, rinsing witha small quantity of diethyl ether to giveN-(4-bromonaphthalen-1-yl)-1H-benzo[d]imidazol-2-amine as a white solid.MS m/z=338 [M+1]⁺. Calc'd for C₁₇H₁₂BrN₃: 337

Step 3N-(4-(2-(2-aminopyrimidin-5-yl)ethynyl)naphthalen-1-yl)-1H-benzo[d]imidazol-2-amine

The title compound was prepared in a manner to that described inexperimental procedure A1 step 2. MS m/z=377 [M+1]⁺. Calc'd forC₂₃H₁₆N₆: 376

Example 77-V-1

Synthesis of(R)-5-(2-(2-aminopyrimidin-5-yl)ethynyl)-2-fluoro-N-(2-(3-hydroxypiperidin-1-yl)-5-(trifluoromethyl)phenyl)benzamideStep 1: Preparation of(R)-1-(2-nitro-4-(trifluoromethyl)phenyl)piperidin-3-ol

To a 100-mL round bottom flask (RBF) was added (R)-piperidin-3-olhydrochloride (1.29 g, 9.37 mmol), sodium bicarbonate (2.76 g, 32.8mmol), THF and 1-fluoro-2-nitro-4-(trifluoromethyl)benzene (1.31 ml,9.37 mmol). The yellow mixture was heated to 75° C. with a water-cooledreflux condensor and allowed to stir 14 h. The reaction was filteredthrough a glass frit, rinsing with EtOAc, and concentrated in vacuo togive (R)-1-(2-nitro-4-(trifluoromethyl)phenyl)piperidin-3-ol as anorange oil.

Step 2: Preparation of(R)-3-(tert-butyldimethylsilyloxy)-1-(2-nitro-4-(trifluoromethyl)phenyl)piperidine

To a solution of (R)-1-(2-nitro-4-(trifluoromethyl)phenyl)piperidin-3-ol(3.35 g, 11.5 mmol) and imidazole (1.02 g, 15.0 mmol) in DMF at ambienttemperature under nitrogen was added tert-butyldimethylsilylchloride(1.91 g, 12.7 mmol). The reaction was allowed to stir for 24 h, at whichpoint additional 0.3 g tert-butyldimethylsilylchloride was added. Thereaction was allowed to stir for an additional 14 h, and was then pouredinto Et₂O/saturated aqueous NaHCO₃. The organic layer was washed 2×H₂O,1×brine, dried over anhydrous MgSO₄, filtered and concentrated to ayellow oil. The crude material was treated with hexanes and adsorbedonto silica gel and passed through a Redi-Sep® pre-packed silica gelcolumn (80 g) eluting with 0-20% EtOAc/hexane. The product-containingfractions were concentrated to afford(R)-3-(tert-butyldimethylsilyloxy)-1-(2-nitro-4-(trifluoromethyl)phenyl)piperidineas a yellow oil. MS m/z=405 [M+H]⁺. Calc'd for C₁₈H₂₇F₃N₂O₃Si: 404.

Step 3: Preparation of(R)-2-(3-(tert-butyldimethylsilyloxy)piperidin-1-yl)-5-(trifluoromethyl)benzenamine

A 200 mL RBF was charged with(R)-3-(tert-butyldimethylsilyloxy)-1-(2-nitro-4-(trifluoromethyl)phenyl)piperidine(4.10 g, 10.1 mmol) and palladium, 10 wt. % on activated carbon wet(0.179 ml, 2.03 mmol) under nitrogen. MeOH was added via syringe, andthe atmosphere replaced with hydrogen via one or more balloons. Thereaction was stirred rapidly for 60 h. The reaction was flushed withnitrogen, filtered through celite rinsing with 100 mL MeOH, andconcentrated in vacuo. The crude material was treated with hexanes andpassed through a Redi-Sep® pre-packed silica gel column (80 g) elutingwith 0-40% EtOAc/hexane. The product-containing fractions wereconcentrated to afford(R)-2-(3-(tert-butyldimethylsilyloxy)piperidin-1-yl)-5-(trifluoromethyl)benzenamineas a brown oil. MS m/z=375 [M+H]⁺. Calc'd for C₁₈H₂₉F₃N₂OSi: 374.

Step 4: Preparation of(R)-N-(2-(3-(tert-butyldimethylsilyloxy)piperidin-1-yl)-5-(trifluoromethyl)phenyl)-2-fluoro-5-iodobenzamide

In a vial,(R)-2-(3-(tert-butyldimethylsilyloxy)piperidin-1-yl)-5-(trifluoromethyl)benzenamine(0.517 g, 1.4 mmol) was taken up in THF. Triethylamine (0.29 ml, 2.1mmol) and 2-fluoro-5-iodobenzoyl chloride (0.43 g, 1.5 mmol) were added.The vial was sealed and the reaction stirred for 48 h. The reactionmixture was poured into EtOAc/1N NaOH. The organic layer was dried overanhydrous sodium sulfate and concentrated in vacuo. The crude materialwas treated with hexanes and passed through a Redi-Sep® pre-packedsilica gel column (40 g) eluting with 0-10% EtOAc/hexane. Theproduct-containing fractions were concentrated to afford(R)-N-(2-(3-(tert-butyldimethylsilyloxy)piperidin-1-yl)-5-(trifluoromethyl)phenyl)-2-fluoro-5-iodobenzamideas a white foam.

Step 5: Preparation of(R)-5-(2-(2-aminopyrimidin-5-yl)ethynyl)-N-(2-(3-(tert-butyldimethylsilyloxy)piperidin-1-yl)-5-(trifluoromethyl)phenyl)-2-fluorobenzamide

In a 16×120 mm resealable pyrex tube, 5-ethynylpyrimidin-2-amine (0.080g, 0.67 mmol),(R)-N-(2-(3-(tert-butyldimethylsilyloxy)piperidin-1-yl)-5-(trifluoromethyl)phenyl)-2-fluoro-5-iodobenzamide(0.210 g, 0.34 mmol), Bis(triphenylphosphine)palladium(II) dichloride(0.012 g, 0.017 mmol), and Copper(I) iodide (0.0032 g, 0.017 mmol) weretaken up in CH₃CN and Triethylamine (0.71 ml, 5.1 mmol) was added, andthe tube was flushed with nitrogen. The tube was sealed and the reactionheated to 70° C. overnight. The reaction was cooled, and transferred toa 50 mL RBF with EtOAc. The mixture was concentrated in vacuo, and theresulting solid was treated with 10% MeOH in CH₂Cl₂ and adsorbed onto1.5 g silica gel and passed through a Redi-Sep®D pre-packed silica gelcolumn (40 g) eluting with 0-60% EtOAc/hexane. The product-containingfractions were concentrated to afford(R)-5-(2-(2-aminopyrimidin-5-yl)ethynyl)-N-(2-(3-(tert-butyldimethylsilyloxy)piperidin-1-yl)-5-(trifluoromethyl)phenyl)-2-fluorobenzamideas an off-white solid.

Step 6: Preparation of(R)-5-(2-(2-aminopyrimidin-5-yl)ethynyl)-2-fluoro-N-(2-(3-hydroxypiperidin-1-yl)-5-(trifluoromethyl)phenyl)

To a yellow solution of(R)-5-(2-(2-aminopyrimidin-5-yl)ethynyl)-N-(2-(3-(tert-butyldimethylsilyloxy)piperidin-1-yl)-5-(trifluoromethyl)phenyl)-2-fluorobenzamide(0.162 g, 0.264 mmol) was added tetrabutylammonium fluoride, 1.0 M inTHF (0.688 ml, 2.38 mmol). The reaction was allowed to stir for 6 h, atwhich point it was found by TLC analysis to be complete. The reactionwas diluted with EtOAc and washed once with brine. The organic layer wasdried over anhydrous sodium sulfate and concentrated in vacuo to give ayellow oil, which was purified by silica gel chrmatography, 0-10%MeOH/MC to give(R)-5-(2-(2-aminopyrimidin-5-yl)ethynyl)-2-fluoro-N-(2-(3-hydroxypiperidin-1-yl)-5-(trifluoromethyl)phenyl)benzamideas an off-white solid. MS m/z=500 [M+H]⁺. Calc'd for C₂₅H₂₁F₄N₅O₂: 499.

Example 77-V-2

Synthesis of5-(2-(2-aminopyrimidin-5-yl)ethynyl)-2-methoxy-N-(2-(piperidin-1-yl)-5-(trifluoromethyl)phenyl)benzamide

A mixture of5-(2-(2-aminopyrimidin-5-yl)ethynyl)-2-fluoro-N-(2-(piperidin-1-yl)-5-(trifluoromethyl)phenyl)benzamide(0.14 g, 0.29 mmol) and NaOMe (0.5 M solution in methanol, 2.0 mL, 1.0mmol) in a sealed tube was heated to reflux. After 16 h, the reactionwas cooled and partitioned between EtOAc and brine. The organic layerwas dried over anhydrous sodium sulfate, filtered, and concentrated. Thematerial was purified by preparative TLC, eluting with 30%acetone/dichloromethane to give5-(2-(2-aminopyrimidin-5-yl)ethynyl)-2-methoxy-N-(2-(piperidin-1-yl)-5-(trifluoromethyl)phenyl)benzamideas a white solid. MS m/z=496 [M+H]⁺. Calc'd for C₂₆H₂₄F₃N₅O₂: 495.

Example 77-V-3

Synthesis of(S)-5-(2-(2-aminopyrimidin-5-yl)ethynyl)-2-fluoro-N-(2-(3-(methylamino)piperidin-1-yl)-5-(trifluoromethyl)phenyl)benzamideStep 1: Preparation of (S)-tert-butylmethyl(1-(2-nitro-4-(trifluoromethyl)phenyl)piperidin-3-yl)carbamate

To an orange solution of (S)-tert-butyl1-(2-nitro-4-(trifluoromethyl)phenyl)piperidin-3-ylcarbamate (1.50 g,3.9 mmol) in DMF at 0 deg. C. was added sodium hydride, 60% dispersionin mineral oil (0.19 g, 4.8 mmol). Bubbling was observed, and thesolution became darker orange. After about 20 min, iodomethane (0.30 ml,4.8 mmol) was added dropwise via syringe. The orange mixture was allowedto warm to room temperature over 30 min. Water was added, followed bydiethyl ether. The organics were washed 1×H₂O, 1×brine, dried overanhydrous Na₂SO₄, filtered, and concentrated to give (S)-tert-butylmethyl(1-(2-nitro-4-(trifluoromethyl)phenyl)piperidin-3-yl)carbamate asan orange semi-solid which was used without further purification. MSm/z=404 [M+H]⁺. Calc'd for C₁₈H₂₄F₃N₃O₄: 403.

Step 2: Preparation of (S)-tert-butyl1-(2-amino-4-(trifluoromethyl)phenyl)piperidin-3-yl(methyl)carbamate

To a 100 mL RBF was added (S)-tert-butylmethyl(1-(2-nitro-4-(trifluoromethyl)phenyl)piperidin-3-yl)carbamate(1.75 g, 4.34 mmol) and palladium, 10 wt. % on activated carbon wet(0.923 g, 0.868 mmol) under nitrogen. MeOH was added via syringe, andthe atmosphere was purged with hydrogen from a balloon. The reaction wasallowed to stir rapidly under hydrogen for 8 h. The flask was purgedwith nitrogen, filtered through celite, rinsing with 100 mL MeOH, andconcentrated to give (S)-tert-butyl1-(2-amino-4-(trifluoromethyl)phenyl)piperidin-3-yl(methyl)carbamate asa gray solid. MS m/z=374 [M+H]⁺. Calc'd for C₁₈H₂₆F₃N₃O₂: 373.

Step 3: Preparation of (S)-tert-butyl1-(2-(2-fluoro-5-iodobenzamido)-4-(trifluoromethyl)phenyl)piperidin-3-yl(methyl)carbamate

In a vial, (S)-tert-butyl1-(2-amino-4-(trifluoromethyl)phenyl)piperidin-3-yl(methyl)carbamate(0.500 g, 1.3 mmol) was taken up in CH2Cl2. The solution was cooled to 0deg. C. and Triethylamine (0.24 ml, 1.7 mmol) and 2-fluoro-5-iodobenzoylchloride (0.42 g, 1.5 mmol) were added. The tube was sealed and thereaction stirred for 2 h. The reaction mixture was poured into EtOAc/1NNaOH. The organic layer was dried over anhydrous sodium sulfate andconcentrated in vacuo. The resulting off-white-foam (S)-tert-butyl1-(2-(2-fluoro-5-iodobenzamido)-4-(trifluoromethyl)phenyl)piperidin-3-yl(methyl)carbamatewas used without further purification. MS m/z=622 [M+H]⁺. Calc'd forC₂₅H₂₈F₄IN₃O₃: 621.

Step 4: Preparation of (S)-tert-butyl1-(2-(5-(2-(2-aminopyrimidin-5-yl)ethynyl)-2-fluorobenzamido)-4-(trifluoromethyl)phenyl)piperidin-3-yl(methyl)carbamate

In a 25-mL RBF (S)-tert-butyl1-(2-(2-fluoro-5-iodobenzamido)-4-(trifluoromethyl)phenyl)piperidin-3-yl(methyl)carbamate(0.496 g, 0.80 mmol), 5-ethynylpyrimidin-2-amine (0.19 g, 1.6 mmol),Bis(triphenylphosphine)palladium(II) dichloride (0.028 g, 0.040 mmol),and Copper(I) iodide (0.0076 g, 0.040 mmol) were taken up in CH₃CN andTriethylamine (1.7 ml, 12 mmol) was added, and the tube was flushed withnitrogen. The tube was sealed and the reaction heated to 70 deg. C. for16 h. The reaction was cooled and transfered to a larger flask withEtOAc and concentrated in vacuo. The solid was adsorbed onto 4 g silicagel from 10% MeOH/MC purified by Isco {Redi-Sep® pre-packed silica gelcolumn (80 g); eluent 0-75% EtOAc/hexanes over 30 min}.Product-containing fractions were concentrated to afford (S)-tert-butyl1-(2-(5-(2-(2-aminopyrimidin-5-yl)ethynyl)-2-fluorobenzamido)-4-(trifluoromethyl)phenyl)piperidin-3-yl(methyl)carbamateas a orange foam. MS m/z=613 [M+H]⁺. Calc'd for C₃₁H₃₂F₄N₆O₃: 612.

Step 5: Preparation of(S)-5-(2-(2-aminopyrimidin-5-yl)ethynyl)-2-fluoro-N-(2-(3-(methylamino)piperidin-1-yl)-5-(trifluoromethyl)phenyl)benzamide

To a yellow solution of (S)-tert-butyl1-(2-(5-(2-(2-aminopyrimidin-5-yl)ethynyl)-2-fluorobenzamido)-4-(trifluoromethyl)phenyl)piperidin-3-yl(methyl)carbamate(0.397 g, 0.65 mmol) in 3 mL dioxane at 0 deg. C. was added hydrogenchloride 4.0 M in dioxane (1.6 ml, 6.5 mmol). The reaction was allowedto warm to ambient temp, as the clump, which formed would not go intosolution. 3 mL of CH₂Cl₂, was added followed by 5 mL MeOH to give ahomogenous yellow solution. After 30 min, the solution was concentratedin vacuo to give a yellow solid, which was treated with 1N NaOH andEtOAc. The organic layer was washed twice with 1N NaOH, dried overanhyd. Na₂SO₄, filtered, and concentrated in vacuo to give(S)-5-(2-(2-aminopyrimidin-5-yl)ethynyl)-2-fluoro-N-(2-(3-(methylamino)piperidin-1-yl)-5-(trifluoromethyl)phenyl)benzamideas a light yellow solid. MS m/z=513 [M+H]⁺. Calc'd for C₂₆H₂₄F₄N₆O: 512.

Example 77-V-4

Synthesis of(S)-N-(2-(3-aminopiperidin-1-yl)-5-(trifluoromethyl)phenyl)-5-(2-(2-aminopyrimidin-5-yl)ethynyl)-2-fluorobenzamide

The title compound was synthesized in a manner analogous to thatdescribed in Example 77-V-3. MS m/z=499 [M+H]⁺. Calc'd for C₂₅H₂₂F₄N₆O:498.

Experiental Method B

Example 78

Synthesis ofN-(4-(2-(2-aminopyrimidin-5-yl)ethynyl)-3-methylphenyl)-3-(trifluoromethyl)benzamideStep 1: Preparation ofN-(4-iodo-3-methylphenyl)-3-(trifluoromethyl)benzamide

To a solution of 4-iodo-3-methyl aniline (200 mg, 0.86 mmol) and^(i)Pr₂NEt (0.19 mL, 0.95 mmol) in CH₂Cl₂ (10 mL) was added3-(trifluoromethyl)benzoyl chloride (0.133 mL, 0.90 mmol). The mixturewas allowed to stir at room temperature for 0.5 h at which time it wasdiluted with CH₂Cl₂ (20 mL). The organic layer was washed with aq. HCl(10 mL, 1 M), 9% aq. Na₂CO₃ (10 mL), brine, dried over anhydrous sodiumsulfate, filtered and concentrated under reduced pressure. The resultingoil was used without further purification.

Step 2:N-(4-(2-(2-aminopyrimidin-5-yl)ethynyl)-3-methylphenyl)-3-(trifluoromethyl)benzamide

The title compound was prepared in a manner similar to that describedExperimental Method A1, Example 1-step 2. MS m/z=397 [M+H]⁺. Calc'd forC₂₁H₁₅F₃N₄O: 396

The following Examples 79-80 were prepared by a method similar to thatdescribed in Experimental Method B and Example 78.

Example MS Data MS Data No. Structure Method MW M + 1 M − 1 79

B1 450.34 451 80

B1 396.37 397

Experimental Method C1

Example 81

Synthesis of1-(4-(2-(2-aminopyrimidin-5-yl)ethynyl)-3-methylphenyl)-3-(3-(trifluoromethyl)phenyl)ureaStep 1: 1-(4-iodo-3-methylphenyl)-3-(3-(trifluoromethyl)phenyl)urea

To a solution of 4-iodo-3-methylaniline (200 mg, 0.86 mmol) in benzene(5 mL) in a sealable tube was added1-isocyanato-3-(trifluoromethyl)benzene (0.133 mL, 0.94 mL; “E” is anelectrophilic group disussed in scheme 3, and here is an isocyanate).The tube was sealed and heated at 90° C. for 4 h. The mixture wasallowed to cool to room temperature before filtering. The off whitesolid was washed with additional benzene (10 mL) and used withoutfurther purification.

Step 2:1-(4-(2-(2-aminopyrimidin-5-yl)ethynyl)-3-methylphenyl)-3-(3-(trifluoromethyl)phenyl)urea

The title compound was prepared in a manner similar to that describedExperimental Method A1, Example 1-step 2. MS m/z=412 [M+H]⁺. Calc'd forC₂₁H₁₆F₃N₅O: 411

The following Example 82 was prepared by a method similar to thatdescribed in Experimental Method C1 and Example 81.

Example MS Data MS Data No. Structure Method MW M + 1 M − 1 82

C1 361.38 362

Experimental Method D

Example 83

Synthesis of4-methyl-N-(3-((4-methylpiperazin-1-yl)methyl)-5-(trifluoromethyl)phenyl)-3-(2-(quinoxalin-2-yl)ethynyl)benzamideStep 1.: Preparation of3-iodo-4-methyl-N-(3-((4-methylpiperazin-1-yl)methyl)-5-(trifluoromethyl)phenyl)benzamide

The title compound was made in manner similar to that described inExample 2, Step 1.

Step 2: Preparation of3-ethynyl-4-methyl-N-(3-((4-methylpiperazin-1-yl)methyl)-5-(trifluoromethyl)phenyl)benzamide

To a mixture of3-iodo-4-methyl-N-(3-((4-methylpiperazin-1-yl)methyl)-5-(trifluoromethyl)phenyl)benzamide(951 mg, 1.84 mmol), PdCl₂(PPh₃)₂ (65 mg, 0.092 mmol) in MeCN (75 mL)and Et₃N (20 mL) at room temperature was added trimethylsilylacetylene(0.8 mL, 5.52 mmol) followed by CuI (18 mg, 0.092 mmol). The resultingmixture was allowed to stir at room temperature for 2 h at which timethe reaction mixture was concentrated under reduced pressure followed byreconstitution in MeOH (100 mL). To this mixture was added enough K₂CO₃to saturate the mixture and the mixture was allowed to stir for about1.5 h. The mixture was filtered through a pad of Celite. To the filtratewas added silica gel (˜20 mL) and the mixture was concentrated underreduced pressure, and purified via automated flash chromatography(silica gel, 0% to 15% MeOH in CH₂Cl₂, gradient elution) to afford3-ethynyl-4-methyl-N-(3-((4-methylpiperazin-1-yl)methyl)-5-(trifluoromethyl)phenyl)benzamide.

Step 3:4-methyl-N-(3-((4-methylpiperazin-1-yl)methyl)-5-(trifluoromethyl)phenyl)-3-(2-(quinoxalin-2-yl)ethynyl)benzamide

To a solution of 2-bromoquinoxaline (96 mg, 0.46 mmol),3-3-ethynyl-4-methyl-N-(3-((4-methylpiperazin-1-yl)methyl)-5-(trifluoromethyl)phenyl)benzamide(174 mg, 0.42 mmol), PdCl₂(PPh₃)₂ (15 mg, 0.021 mmol) in MeCN (10 mL)and Et₃N (3 mL) in a sealable tube was added CuI (4 mg, 0.021 mmol). Thetube was sealed and heated at 90° C. for 1 h. The reaction mixture wascooled to room temperature and concentrated under reduced pressure. Theresulting solid was absorbed onto silica gel (5 mL) and purified viaautomated flash chromatography (silica gel, 0 to 5% MeOH in CH₂Cl₂,gradient elution) to afford4-methyl-3-(2-(quinolin-3-yl)ethynyl)-N-(3-(trifluoromethyl)phenyl)benzamide.MS m/z=544 [M+H]⁺. Calc'd for C₃₁H₂₈F₃N₅O: 543

The following Examples 84-92 were prepared by a method similar to thatdescribed in Experimental Method D and Example 83.

Example MS Data MS Data No. Structure Method MW M + 1 M − 1 84

D1 421.38 422 85

D1 437.42 438 86

D1 420.39 421 87

D1 543.59 544 88

D1 544.57 545 89

D1 550.58 551 90

D1 533.55 534 91

D1 542.6 543 92

D1 431 432

Provided below are exemplary building block starting materials andintermediates, generally not commercially available, which may beutilized in Experimental Methods A-D above. Below are procedures andexamples for building various of the exemplary building blocks.

Various different A rings (R¹¹ and R¹⁴ groups), which are contemplatedherein, may be made by various methods, as represented by Examples93-160 below.

Example 93

Synthesis of(4-methylpiperazin-1-yl)(3-nitro-5-trifluoromethyl)phenyl)-methanone

Step 1: A solution of thionyl chloride (30 ml) and3-nitro-5-(trifluoromethyl)benzoic acid (10 g) was heated to reflux for2 h. The reaction mixture was concentrated under reduced pressure andazeotroped with toluene (10 ml—removed under reduced pressure) to afford3-nitro-5-(trifluoromethyl)benzoyl chloride.Step 2: To a solution of 3-nitro-5-(trifluoromethyl)benzoyl chloride(2.35 g, 9.3 mmol) in CH₂Cl₂ (40 ml) at room temperature was addedN-methylpiperazine (1.26 ml, 9.3 mmol) and the mixture was allowed tostir for 30 min. The reaction was concentrated under reduced pressure,taken up in 1 M HCl (50 ml) and the aqueous layer was washed with Et₂O(2×20 ml). The aqueous layer was basified to a pH of about 9 with 6NNaOH and extracted with Et₂O (3×50 ml). The organic extracts werecombined and washed with water (1×20 ml) followed by brine (1×20 ml),dried over anhydrous sodium sulfate, filtered and concentrated underreduced pressure to afford(4-methylpiperazin-1-yl)(3-nitro-5-trifluoromethyl)phenyl)-methanone asa tan oil. MS m/z=318 [M+H]⁺; Calc'd for C₁₃H₁₄F₃N₃O₃: 317.3.

Example 94

Synthesis of(3-amino-5-(trifluoromethyl)phenyl)(4-methylpiperazin-1-yl)methanone

To an argon purged solution of(4-methylpiperazin-1-yl(3-nitro-5-trifluoromethyl)phenyl)-methanone(1.03 g, 3.25 mmol) was added Pd/C (344 mg, 0.32 mmol, 10%). The mixturewas placed under an atmosphere of H₂ for 5 h. The reaction was purgedwith argon and filtered through Celite. The filtrate was concentratedunder reduced pressure to afford(3-amino-5-(trifluoromethyl)phenyl)(4-methylpiperazin-1-yl)methanone asan off-white solid. MS m/z=288.1 [M+H]⁺. Calc'd for C₁₃H₁₆F₃N₃O: 287.3.

Example 95

Synthesis of3-((4-methylpiperazin-1-yl)methyl)-5-(trifluoromethyl)-benzenamine

To LAH (1.84 g, 48.5 mmol) in THF (50 ml) at room temperature was added(4-methylpiperazin-1-yl)(3-nitro-5-trifluoromethyl)phenyl)-methanone(1.54 g, 4.85 mmol) in THF (10 ml). The resulting mixture was refluxedfor 5 h. The reaction mixture was cooled to 0° C. at which point water(1.84 ml), 15% aq. NaOH (1.84 ml) and water (3.68 ml) were successivelyadded. The resulting mixture was allowed to stir at room temperature for1 h. The mixture was filtered through Celite, concentrated under reducedpressure and purified via flash chromatography (silica gel, 0 to 25%MeOH in CH₂Cl₂, gradient elution) to afford3-((4-methylpiperazin-1-yl)methyl)-5-(trifluoromethyl)benzenamine as acolorless oil. MS m/z=274 [M+H]⁺; Calc'd for C₁₃H₁₆F₃N₃O: 273.3.

Example 96

Synthesis of 3-(4-methylpiperazin-1-yl)-5-(trifluoromethyl)benzenamineStep 1: Preparation of1-methyl-4-(3-nitro-5-(trifluoromethyl)phenyl)piperazine

Into a 50 mL round bottom flask was placed the1-iodo-3-nitro-5-(trifluoromethyl)benzene (1 g, 3.15 mmol),N-methylpiperazine (0.379 g, 3.78 mmol),bis(dibenzylideneacetone)palladium (0.029 g, 0.0315 mmol), sodiumtert-butoxide (0.424 g, 4.416 mmol),2-dicyclohexyl-2′-(N,N-dimethylamino)biphenyl (0.037 g, 0.094 mmol), andtoluene (25 mL). Reaction was heated to 80° C. with stirring for 20hours. Reaction was cooled to room temperature and water (1 mL) andethyl acetate (10 mL) were added. The organic layer is separated,concentrated under reduced pressure and purified via silica columneluting with 0 to 20% methanol in dichloromethane. The title compoundwas obtained as an orange oil.

Step 2. Preparation of3-(4-methylpiperazin-1-yl)-5-(trifluoromethyl)benzenamine

Into a 100 mL round bottom flask under inert atmosphere was placed1-methyl-4-(3-nitro-5-(trifluoromethyl)phenyl)piperazine (0.736 g, 2.54mmol), 10% palladium on carbon (90 mg), ethanol (40 mL), and acetic acid(20 mL). The atmosphere was exchanged with hydrogen gas via balloon. Thereaction was allowed to stir 3 days at room temperature, then filteredthrough celite and concentrated under reduced pressure to afford thecrude as an orange oil. The crude mixture was purified via silica columnchromatography with a solvent solution of 90%/10%/1% ratio ofCH₂Cl₂/CH₃OH/NH₄OH, to afford the title compound. MS m/z=260 [M+H]⁺;Calc'd for C₁₂H₁₆F₃N₃: 259.3.

Example 97

Step 1: Synthesis of 1-isopropyl-4-(4-nitrophenyl)piperazine

To a vial was added 4-fluoronitrobenzene (1.41 g, 1.06 mL, 0.01 mol),N,N-diisopropylethylamine (1.92 mL, 0.011 mmol), isopropylpiperazine(1.41 g, 0.011 mmol), and N,N-dimethylformamide (10 mL). Mixture washeated at 100° C. for 48 h in a sealed tube. The reaction mixture wascooled to room temperature and concentrated. The residue was purifiedvia silica gel column chromatography (gradient elution with 0 to 10%methanol in dichloromethane) to afford1-isopropyl-4-(4-nitrophenyl)piperazine.

Step 2: Synthesis of 4-(4-isopropylpiperazin-1-yl)benzenamine

10% Palladium on carbon (0.05 g) was added to a solution of thenitroaniline (0.001 mol) in ethanol (50 mL) under a H₂(g) atmosphere(via balloon). The reaction mixture stirred at RT overnight and thenfiltered through celite. The filtrate was concentrated to afford a darkyellow oil, which was purified via silica column chromatography using anisocratic solvent system of 100% (90/10/1) (CH₂Cl₂/CH₃OH/NH₄OH) toisolate the title compound. MS m/z=220 [M+H]⁺; Calc'd for C₁₃H₂₁N₃:219.3.

Example 98

Synthesis of(1-(2-amino-4-(trifluoromethyl)phenyl)-1H-imidazol-4-yl)methanol Step 1:(1-(2-nitro-4-(trifluoromethyl)phenyl)-1H-imidazol-4-yl)methanol

To a solution of 1-fluoro-2-nitro-4-(trifluoromethyl)benzene (1.04 mL,7.43 mmol) and (1H-pyrrol-3-yl)methanol hydrochloride salt (1.0 g, 7.43mmol) in DMF (10 mL) was added Na₂CO₃ (2.36 g, 22.3 mmol). The resultingmixture was heated at 70° C. overnight. The mixture was cooled to roomtemperature and concentrated under reduced pressure. The mixture wasreconstituted in EtOAc (50 mL) and washed with 9% aq. Na₂CO₃ (10 mL),brine (10 mL), dried over anhydrous sodium sulfate, filtered andconcentrated under reduced pressure to afford(1-(2-nitro-4-(trifluoromethyl)phenyl)-1H-imidazol-4-yl)methanol.

Step 2: (1-(2-amino-4-(trifluoromethyl)phenyl)-1H-imidazol-4-yl)methanol

To a solution of(1-(2-nitro-4-(trifluoromethyl)phenyl)-1H-imidazol-4-yl)methanol (167mg, 0.58 mmol) in EtOH (10 mL) was added a slurry of Raney Nickel (500mg, washed, wet). The mixture was allowed to stir at room temperatureovernight. Upon completion, the reaction mixture was filtered throughCelite and concentrated to afford(1-(2-amino-4-(trifluoromethyl)phenyl)-1H-imidazol-4-yl)methanol. MSm/z=258 [M+H]⁺. Calc'd for C₁₁H₁₀F₃N₃O: 257.

Example 99

Synthesis ofN-(3-(dimethylamino)propyl)-N-2-methyl-5-(trifluoromethyl)pyridine-2,3-diamineStep 1:N-(3-(dimethylamino)propyl)-N-methyl-3-nitro-5-(trifluoromethyl)pyridin-2-amine

A solution of 3-nitro-5-(trifluoromethyl)pyridin-2-ol (500 mg, 2.4mmol), CHCl₃ (25 mL), oxalyl chloride (0.42 mL, 4.8 mmol) and DMF (1drop) was allowed to reflux for 16 h. Once consumption of startingmaterial was complete the reaction was concentrated under reducedpressure. A portion of the crude material (182 mg, 0.8 mmol) was removedand added to a mixture of N¹,N¹,N³-trimethylpropane-1,3-diamine (0.13mL, 0.88 mmol), K₂CO₃ (221 mg, 1.6 mmol) and heated at 90° C. for 10min. The mixture was concentrated under reduced pressure andreconstituted in CH₂Cl₂ (20 mL). The organic layer was washed with water(10 mL), brine (10 mL), dried over anhydrous sodium sulfate, filteredand concentrated under reduced pressure to affordN-(3-(dimethylamino)propyl)-N-methyl-3-nitro-5-(trifluoromethyl)pyridin-2-amine.MS m/z=307 [M+H]⁺. Calc'd for C₁₂H₁₇F₃N₄O₂: 306.

Step 2:N²-(3-(dimethylamino)propyl)-N²-methyl-5-(trifluoromethyl)pyridine-2,3-diamine

To a solution ofN-(3-(dimethylamino)propyl)-N-methyl-3-nitro-5-(trifluoromethyl)pyridin-2-amine(246 mg, 0.8 mmol) in EtOH was added Raney Nickel (700 mg, wet, washed).The reaction was allowed to stir for 2 h then filtered through a pad ofCelite and concentrated under reduced pressure to affordN²-(3-(dimethylamino)propyl)-N²-methyl-5-(trifluoromethyl)pyridine-2,3-diamine.MS m/z=277 [M+H]⁺. Calc'd for C₁₂H₁₉F₃N₄: 276

Example 100

Synthesis of2-(4-methylpiperazin-1-ylsulfonyl)-5-(trifluoromethyl)benzenamine Step1: 1-methyl-4-(2-nitro-4-(trifluoromethyl)phenylsulfonyl)piperazine

To a solution of 2-nitro-4-(trifluoromethyl)benzene-1-sulfonyl chloride(1.0 g, 1.73 mmol) in CH₂Cl₂ (50 mL) was added 1-methylpiperazine (0.40mL, 3.6 mmol). The resulting mixture was allowed to stir at roomtemperature overnight, then diluted with CH₂Cl₂ (30 mL), the organiclayer was washed with 9% aq. Na₂CO₃ (10 mL) and brine (10 mL). Theorganic layer was dried over anhydrous sodium sulfate, filtered andconcentrated to afford the title compound as a white solid.

Step 2:2-(4-methylpiperazin-1-ylsulfonyl)-5-(trifluoromethyl)benzenamine

1-methyl-4-(2-nitro-4-(trifluoromethyl)phenylsulfonyl)piperazine wasdissolved in EtOH (20 mL) and the solution was purged with argon. Pd/C(365 mg, 0.34 mmol, 10%) was added to the solution, which was stirredfor 3 days in an atmosphere of hydrogen gas. The mixture was againpurged with argon, filtered through Celite and concentrated underreduced pressure to afford2-(4-methylpiperazin-1-ylsulfonyl)-5-(trifluoromethyl)benzenamine. MSm/z=324 [M+H]⁺. Calc'd for C₁₂H₁₆F₃N₃O₂S: 323.

Example 101

Synthesis of(3-amino-5-(trifluoromethyl)phenyl)(sulfonylmorpholino)methanone Step 1:(3-nitro-5-(trifluoromethyl)phenyl)(thiomorpholino)methanone

3-Nitro-5-(trifluoromethyl)benzoic acid (2.96 g, 12.6 mmol) was allowedto reflux in thionyl chloride (6 mL) for 6 h. The resulting solution wasallowed to cool to room temperature and then concentrated under reducedpressure. The resulting solid was taken up in CH₂Cl₂ (20 mL) and^(i)Pr₂Net (2.6 mL, 15.1 mmol) and thiomorpholine (1.4 mL, 13.8 mmol)was added. The reaction was stirred at RT for 1 h and then diluted withCH₂Cl₂ (50 mL). The organic layer was washed with aq. HCl (1M, 25 mL),9% aq. Na₂CO₃ (25 mL), brine, dried over anhydrous sodium sulfate,filtered and concentrated under reduced pressure to afford(3-nitro-5-(trifluoromethyl)phenyl)(thiomorpholino)-methanone.

Step 2:(3-nitro-5-(trifluoromethyl)phenyl)(sulfonylmorpholino)-methanone

To a solution of(3-nitro-5-(trifluoromethyl)phenyl)-(thiomorpholino)methanone (1.56 g,4.88 mmol) in EtOH (50 mL) was added a solution of ammonium molybdatetetrahydrate (602 mg, 0.49 mmol) and hydrogen peroxide (30%, 4.2 mL,43.92 mmol). The resulting mixture was allowed to stir overnight. Oncethe reaction was complete, as observed by TLC (1:1 hexanes:EtOAc), itwas poured onto water (100 mL). The aqueous layer was extracted withCH₂Cl₂ (3×50 mL). The combined organic layers were washed with water (25mL), brine (25 mL), dried over anhydrous sodium sulfate, filtered andconcentrated under reduced pressure to afford(3-nitro-5-(trifluoromethyl)phenyl)(sulfonylmorpholino)methanone.

Step 3:(3-amino-5-(trifluoromethyl)phenyl)(sulfonylmorpholino)-methanone

To an argon purged solution of(3-nitro-5-(trifluoromethyl)phenyl)-(sulfonylmorpholino)methanone (658mg, 1.87 mmol) in EtOH (20 mL) was added Pd/C (198 mg, 0.187 mmol, 10%).The resulting mixture was allowed to stir under an atmosphere ofhydrogen gas for 3 days. The reaction was purged with argon, filteredthrough Celite and concentrated under reduced pressure to afford(3-amino-5-(trifluoromethyl)phenyl)-(sulfonylmorpholino)methanone whichwas used without further purification. MS m/z=323 [M+H]⁺. Calc'd forC₁₂H₁₃F₃N₂O₃S: 322.

Example 102

Synthesis of 1-(thiazol-2-yl)ethanamine

The title compound was prepared by a procedure similar to that describedin J. Chem. Soc. Perkin trans., 2, 1339, 2000 (also described in PCTIntl. Patent Publication No. WO 2003093238 A1). NH₄OAc (38.54 g, 500mmol) was added to 1-(thiazol-2-yl)ethanone (5.0 g, 39.3 mmol) in MeOH(100 ml). The mixture was stirred at RT for 15 min. NaCNBH₄ (1.76 g, 200mmol) was added and the mixture was stirred for 4 d. 30 ml 6N HCl wasadded dropwise with the formation of a solid precipitate. The whitesolid was isolated by filtration then taken up in H₂O and washed withEt₂O. The aqueous solution was then basified to pH of about 10 withNaOH, Extracted with EtOAc and dried over Na₂SO₄. Purification by silicachromatography eluting with 5% MeOH/CH₂Cl₂ afforded1-(thiazol-2-yl)ethanamine. MS m/z=129 [M+H]⁺. Calc'd for C₅H₈N₂S: 128

Example 103

Synthesis of6-chloro-N¹-(3-(dimethylamino)propyl)-N¹-methyl-4-(trifluoromethyl)benzene-1,2-diamine

A heterogeneous mixture of1-chloro-2-fluoro-3-nitro-5-(trifluoromethyl)benzene (1.25 mL, 8.2mmol), K₂CO₃ (3.44 g, 24.6 mmol), N¹,N¹,N³-trimethylpropane-1,3-diamine(1.26 mL, 8.61 mmol) and THF were allowed to stir at room temperaturefor 45 min. The THF was removed under reduced pressure and reconstitutedin EtOAc (50 ml). The organic layer was washed with water (20 ml), brine(20 ml), dried over anhydrous sodium sulfate, filtered and concentratedto an oil. The concentrated oil was taken up in EtOH (20 ml) to whichRaney nickel (2.5 g wet, washed) was added. The reduction was monitoredand after 1 h, another portion of Raney nickel (3.8 g, wet, washed) wasadded. The reaction was allowed to stir for an additional 30 min., andfiltered through Celite, washed with EtOH (10 ml) and concentrated. Thecrude residue was purified via flash chromatography (silica gel,gradient elution 0 to 25% MeOH in CH₂Cl₂) to afford6-chloro-N¹-(3-(dimethylamino)propyl)-N¹-methyl-4-(trifluoromethyl)benzene-1,2-diamineas a yellow oil. MS m/z=310.1 [M+H]⁺. Calc'd for C₁₃H₁₉ClF₃N₃: 309.8.

Example 104

Synthesis ofN-(3-(dimethylamino)propyl)-N-methyl-2-nitro-4-(trifluoromethyl)benzenesulfonamide

To a solution of 2-nitro-4-(trifluoromethyl)benzene-1-sulfonyl chloride(500 mg, 1.73 mmol) in CH₂Cl₂ (5 ml) was addedN¹,N¹,N³-trimethylpropane-1,3-diamine (0.26 ml, 1.8 mmol). The resultingmixture was allowed to stir at room temperature for 20 min. Diluted withCH₂Cl₂ (30 ml) and washed the organic layer with 9% aq. Na₂CO₃ (10 ml)and brine (10 ml). Dried over anhydrous sodium sulfate, filtered andconcentrated to a white solid, which was used without furtherpurification. MS m/z=370.1 [M+H]⁺. Calc'd for C₁₃H₁₈F₃N₃O₄S: 369.4.

Example 105

Synthesis of2-amino-N-(3-(dimethylamino)propyl)-N-methyl-4-(trifluoromethyl)benzenesulfonamide

To an argon purged solution ofN-(3-(dimethylamino)propyl)-N-methyl-2-nitro-4-(trifluoromethyl)benzenesulfonamide(255 mg, 0.69 mmol) in EtOH (10 ml) was added Pd/C (73 mg, 0.069 mmol,10%). The reaction mixture was placed under an atmosphere of H₂ gas andallowed to stir for 2 h. The reaction mixture was purged with argon andfiltered through Celite. The reaction was washed with EtOH (10 ml) andconcentrated under reduced pressure to afford2-amino-N-(3-(dimethylamino)propyl)-N-methyl-4-(trifluoromethyl)benzenesulfonamideas a dark oil. MS m/z=340.1 [M+H]⁺. Calc'd for C₁₃H₂₀F₃N₃O₂S: 339.4.

The following substituted aniline intermediates were prepared in amanner similar to the procedures described in Examples 93-105 andExample 55 of co-pending patent Application Ser. No. 60/569,193:

Cal'd Example Structure Name MS M + H⁺ 106

N1-(3- (dimethylamino)propyl)- N1-methyl-4- (trifluoromethyl)benzene-1,2-diamine: 275 276.1 107

N1-(3- (dimethylamino)propyl)- N1-methylbenzene-1,2- diamine 207 208 108

N1-(3- (dimethylamino)propyl) N1,5-dimethylbenzene- 1,2-diamine: 221 222109

N1-(3- (dimethylamino)propyl)- N1,4,5-trimethylbenzene- 1,2-diamine: 235236 110

N1-(3- (dimethylamino)propyl)- N1,3-dimethyl-4- (trifluoromethyl)benzene-1,2-diamine: 289 290 111

N1-(3- (dimethylamino)propyl)- N1-methyl-5- (trifluoromethyl)benzene-1,2-diamine: 275 276

Example 112

Synthesis of 6-methoxy-2-methyl-3-(trifluoromethyl)benzenamine Step 1:1-methoxy-3-methyl-2-nitro-4-(trifluoromethyl)benzene

1-methoxy-3-methyl-2-nitro-4-(trifluoromethyl)benzene was prepared by aprocedure similar to that described in “Synthesis of 3,6-Disubstituted2-Nitrotoluenes by Methylation of Aromatic Nitro Compounds withDimethylsulfonium Methylide”, Kitano, Masafumi, Ohashi Naohito,Synthetic Communications, 30(23), 4247-4254, 2000. To a suspension ofNaH (60% by wt. in mineral oil, 362 mg, 9.04 mmol) andtrimethylsulfonium iodide (1.84 g, 9.04 mmol) in DMSO (17 ml) and THF(6.7 ml) was added 4-methoxy-3-nitrobenzotrifluoride (1.00 g, 4.52 mmol)as a solution in DMSO (2.7 ml). The reaction mixture was allowed to stirat 10-20° C. for 5 hrs. The reaction mixture was quenched by addition toice water. The aqueous layer was separated and extracted with toluene 7times. The combined organic extracts were washed with brine, dried overMgSO₄, and filtered. The solvent was removed by distillation at reducedpressure. The residue was purified by automated silica gelchromatography (100% hexanes to 98:2 hexanes:ethylacetate) to provide1-methoxy-3-methyl-2-nitro-4-(trifluoromethyl)benzene.

Step 2: 6-methoxy-2-methyl-3-(trifluoromethyl)benzenamine

1-methoxy-3-methyl-2-nitro-4-(trifluoromethyl)benzene (258 mg, 1.10mmol), methanol (11.0 mL), and palladium on carbon (77.4 mg) werecombined in a N₂-purged round bottom flask. A balloon containing H₂ wasaffixed to the flask, and the solution was saturated with H₂ for 2minutes. The reaction mixture was allowed to stir under H₂ atmospherefor 12 hrs. Upon completion, as judged by LCMS, the reaction mixture wasfiltered through a plug of Celite and the solvent was removed in vacuoto afford 6-methoxy-2-methyl-3-(trifluoromethyl)benzenamine. MS m/z=206[M+H]⁺. Calc'd for C₉H₁₀F₃NO: 205.

Example 113

Synthesis of 4-chloro-2-methyl-3-(trifluoromethyl)benzenamine

4-Chloro-2-methyl-3-(trifluoromethyl)benzenamine was prepared by amethod similar to that described in “Preparation of Fused Succinimidesas Modulators of Nuclear Hormone Receptor Function”, Salvati, Mark E. etal., PCT Patent Publication WO 2003062241. MS m/z=210 [M+H]⁺. Calc'd forC₉H₁₀F₃NO: 210.

Example 114

Synthesis of N-(3-amino-2-methylphenyl)-2-morpholinoacetamide Step 1:2-bromo-N-(2-methyl-3-nitrophenyl)acetamide

To a solution of 2-methyl-3-nitroaniline (5.0 g, 32.9 mmol) in 120 ml ofCH₂Cl₂ was added 120 ml of saturated NaHCO₃ and bromoacetyl bromide(2.85 ml, 6.6 g, 32.9 mmol). The reaction was stirred at roomtemperature for 64 hours. The layers were separated, and the organiclayer was washed with water, brine and then dried over MgSO₄. Solventevaporation afforded 2-bromo-N-(2-methyl-3-nitrophenyl)acetamide as ayellow solid.

Step 2: N-(2-methyl-3-nitrophenyl)-2-morpholinoacetamide

2-Bromo-N-(2-methyl-3-nitrophenyl)acetamide (0.5 g, 1.8 mmol) wasdissolved in 15 ml of THF and to this was added morpholine (0.17 g, 2.0mmol) and diisopropylethylamine (0.71 g, 5.5 mmol). The reaction wasstirred at room temperature for 16 hours. The reaction was thenpartitioned between EtOAc and H₂O. The aqueous mixture was extractedwith EtOAc, and the combined organic layers were washed with H₂O, brineand then dried over MgSO₄. Solvent evaporation affordedN-(2-methyl-3-nitrophenyl)-2-morpholinoacetamide as a yellow solid.

Step 3: N-(3-amino-2-methylphenyl)-2-morpholinoacetamide

N-(2-Methyl-3-nitrophenyl)-2-morpholinoacetamide (0.25 g, 0.9 mmol) wasdissolved in 20 ml of MeOH, and to this was added a slurry of 10% Pd/C(0.025 g) in a minimal amount of EtOH. The reaction vessel was evacuatedand purged with H₂, and the reaction was stirred at room temperature for16 hours. The mixture was purged with N₂ for 30 minutes and thenfiltered through a pad of celite. Solvent evaporation affordedN-(3-amino-2-methylphenyl)-2-morpholinoacetamide as a gray solid. MSm/z=250.1 [M+H]⁺; Calc'd for C₁₃H₁₉N₃O₂: 249.

Examples 115-118 were prepared by a method similar to the proceduredescribed in Example 114 above.

Example Structure Name 115

N-(5-amino-2- methylphenyl)-2- morpholinoacetamide 116

N-(3-amino-2- methylphenyl_2- (diethylamino)acetamide 117

1-(6-amino-3,3- dimethylindolin-1-yl)- 2-(diethylamino)ethanone 118

1-(6-amino-3,3- dimethylindolin-1-yl)- 2-morpholinoethanone

Example 119

Synthesis of 3-amino-2,6-difluoro-N-methylbenzamide

2,6-Difluoro-3-nitrophenylacetamide (0.5 g, 2.3 mmol) was dissolved in20 ml of MeOH and to this was added a slurry of 10% Pd/C (0.050 g). Thereaction vessel was evacuated and purged with H₂, and the reaction wasstirred at room temperature for 3 hours. The mixture was purged with N₂,and then filtered through a pad of celite. Solvent evaporation afforded3-amino-2,6-difluoro-N-methylbenzamide as a pink solid.

Example 120

(3-amino-2-fluoro-6-(pyrrolidin-1-yl)phenyl)(pyrrolidin-1-yl)methanone

Example 120 was prepared by a method similar to that described inExample 119 above.

Example 121

Synthesis of 2-methyl-3-((4-methylpiperazin-1-yl)methyl)benzeneamineStep 1: 1-(2-methyl-3-nitrobenzyl)-4-methylpiperazine

2-Methyl-3-nitrobenzylchloride (1.0 g, 5.4 mmol) was dissolved in 30 mlof THF, and to this was added 1-methylpiperazine (0.65 g, 6.5 mmol) andsodium bicarbonate (2.26 g, 26.9 mmol). The reaction mixture was stirredat 65° C. for 16 hours. The mixture was partitioned between EtOAc andH₂O. The aqueous layer was extracted with EtOAc, and the combinedorganic layers were washed with saturated NH₄Cl, H₂O, brine and driedover MgSO₄. Solvent evaporation afforded1-(2-methyl-3-nitrobenzyl)-4-methylpiperazine.

Step 2: 2-methyl-3-((4-methylpiperazin-1-yl)methyl)benzeneamine

1-(2-Methyl-3-nitrobenzyl)-4-methylpiperazine (1.2 g, 4.8 mmol) wasdissolved in 50 ml of MeOH, and to this was added a slurry of 10% Pd/Cin a minimal amount of EtOH. The reaction mixture was evacuated andpurged with H₂, and then stirred at room temperature for 3 hours. Themixture was purged with N₂ for 30 minutes and then filtered through apad of celite. Solvent evaporation afforded2-methyl-3-((4-methylpiperazin-1-yl)methyl)benzeneamine.

Example 122

Synthesis of N-(5-amino-2-tert-butylphenyl)-2-dimethylamino)acetamideStep 1: 2-tert-butyl-5-nitrobenzenamine

Concentrated sulfuric acid (1 L) was cooled to −10° C. with a dryice-isopropanol bath in a 2 L 3-necked round bottom flask fitted with amechanical stirrer and temperature probe. The 2-t-butylaniline (109 g,730 mmol) was added, giving a clumpy solid. Once the temperature of themixture was stabilized at −10° C., the potassium nitrate (101 g, 1001mmol) was added portion wise, as a solid, over a 4-hour period,maintaining the temperature between −20 and −5° C. Once all of thepotassium nitrate was added, the reaction was left to stir overnightwith gradual warming to room temperature. The reaction was quenched bydiluting with water and then extracting three times with EtOAc. TheEtOAc extracts were washed multiple times with saturated NaHCO₃, untilgas evolution ceased, then with brine. The ethyl acetate extracts werethen combined, dried over anhydrous Na₂SO₄, filtered and concentratedunder reduced pressure giving a black oil. The oil was eluted through acolumn of silica gel with EtOAc: hexanes gradient 5-50%. Solventevaporation afforded 2-tert-butyl-5-nitrobenzenamine as a red solid.

Step 2: 2-bromo-N-(2-tert-butyl-5-nitrophenyl)acetamide

2-tert-Butyl-5-nitrobenzenamine (70 g, 359 mmol) and a catalytic amountof DMAP were dissolved into THF (1.5 L) under N₂. Triethylamine (109 g,1077 mmol) was added and the solution was cooled to 0° C. Bromoacetylbromide (207 g, 1023 mmol) was then added and the reaction was stirredat room temperature for 16 hours. The reaction was then partiallyconcentrated under reduced pressure, treated with water, and extractedthree times with EtOAc. The EtOAc extracts were washed with brine,combined, dried over Na₂SO₄ and concentrated to a black oil. This oilwas purified using silica chromatography, 95:5:0.5 CH₂Cl₂:MeOH:NH₄OH,giving 2-bromo-N-(2-tert-butyl-5-nitrophenyl)acetamide as a brown solid.

Step 3: N-(2-tert-butyl-5-nitrophenyl)-2-(dimethylamino)acetamide

2-Bromo-N-(2-tert-butyl-5-nitrophenyl)acetamide (80 g, 253, mmol) andpotassium carbonate (70 g, 506 mmol) were combined in THF (1.75 L), andthe mixture was cooled to 0° C. N,N-Dimethylamine (40 ml of a 2 Msolution in THF, 800 mmol) was then added to the mixture through anaddition funnel over a 30-minute period. The mixture was then stirred atroom temperature for 16 hours. The mixture was then filtered and thefiltrate was concentrated. The crude material was purified by silicachromatography using 50% EtOAc:hexanes as the eluent to giveN-(2-tert-butyl-5-nitrophenyl)-2-(dimethylamino)acetamide as a brownsolid.

Step 4: N-(5-amino-2-tert-butylphenyl)-2-dimethylamino)acetamide

To a solution ofN-(2-tert-butyl-5-nitrophenyl)-2-(dimethylamino)acetamide in 1,4-dioxanewas added 10% Pd/C as a slurry in a minimal amount of EtOH. The mixturewas evacuated and purged with H₂, and then stirred at room temperaturefor 16 hours. The reaction was then purged with N₂ and filtered throughcelite. The filtrate was concentrated and purified using silicachromatography, 97.5:2.5:0.25 to 95:5:0.5 CH₂Cl₂:MeOH:NH₄OH, to affordN-(5-amino-2-tert-butylphenyl)-2-dimethylamino)acetamide as a brownsolid. MS (m/z)=250.2 (M+H⁺); Calculated for C₁₄H₂₃N₃O: 249.4

Example 123

Synthesis ofN,N-dimethyl-3-(2-nitro-4-(trifluoromethyl)phenoxy)propan-1-amine Step1: 2-(3-(dimethylamino)propoxy)-5-(trifluoromethyl)benzenamine

A suspension of NaHCO₃ (3.9 g, 48 mmol),1-fluoro-2-nitro-4-trifluoromethylbenzene (4.0 g, 19 mmol), and3-dimethylamino-1-propanol (2.5 ml, 21 mmol) in 38 mL dry THF was heatedwith a reflux condenser under nitrogen for 12 h. The mixture wasfiltered through a fritted funnel into a flask. The solution was cooledto 0° C. and was treated with potassium tert-butoxide (2.4 g, 21 mmol)resulting in an orange solution. The solution was warmed to ambienttemperature and was allowed to stir for 1 h. The solvent was removed invacuo, and the resulting brown oil was partitioned between saturatedaqueous NaHCO₃ and methylene chloride. The aqueous layer was extractedthree times with methylene chloride. The combined organic layers weredried with Na₂SO₄, filtered, and concentrated. The residue was purifiedby silica gel chromatography (MC/MeOH/conc. NH₄OH) to provide thedesired compound as an orange oil. MS (m/z): 293.1 (M+H)⁺. Calc'd forC₁₂H₁₅F₃N₂O₃: 292.25.

Step 2:N,N-dimethyl-3-(2-nitro-4-(trifluoromethyl)phenoxy)propan-1-amine

To 2-(3-(dimethylamino)propoxy)-5-(trifluoromethyl)benzenamine (1.6 g,5.5 mmol) was added Pd/C (10%, 0.58 g) under nitrogen. Methanol (18 ml)was added via syringe, and H₂ gas was introduced and the mixture stirredvigorously under an atmosphere of H₂. After 23 h, the mixture wasfiltered through celite and concentrated to afford the title compound asa light brown solid. MS (m/z): 263 (M+H)⁺. Calc'd for C₁₂H₁₇F₃N₂O₃:262.27.

Example 124

Synthesis of1-(2-amino-4-(trifluoromethyl)phenyl)-N,N-dimethylpiperidin-4-amine Step1: 1-benzyl-N,N-dimethylpiperidin-4-amine dihydrochloride

To a mixture of 4-amino-1-benzyl piperidine (5.0 g, 26 mmol), NaBH₃CN(3.3 g, 53 mmol), AcOH (7.5 ml, 132 mmol) in 130 ml MeOH at 0° C. undernitrogen was added formaldehyde (37 wt % in water, 5.3 mL) as a solutionin 15 ml MeOH slowly dropwise via a pressure-equalized addition funnelover 15 min. The resulting clear solution was allowed to warm to roomtemperature and was allowed to stir for approximately 60 h. The reactionwas quenched by the addition of 20 ml saturated aqueous potassiumcarbonate. The mixture was concentrated in vacuo, and water and EtOAcwas added. The organic layer was removed, and the aqueous layer wasextracted twice with EtOAc. The combined organic layers were dried withNa₂SO₄, filtered, and concentrated to give a cloudy oil, which wasdissolved in methylene chloride and filtered through a fritted funnel.The solvent was removed to give a waxy solid, which was purified bysilica gel chromatography (MC/MeOH/conc. NH₄OH). The resulting materialwas dissolved in diethyl ether, cooled to 0° C. and treated with 20 ml4N HCl in dioxane. The solvent was removed in vacuo to give the desiredproduct as a white solid. MS (m/z): 219.1 (M+H)⁺. Calc'd for C₁₄H₂₂N₂:218.34.

Step 2:N,N-dimethyl-1-(2-nitro-4-(trifluoromethyl)phenyl)piperidin-4-amine

To 1-benzyl-N,N-dimethylpiperidin-4-amine dihydrochloride (6.7 g, 23mmol) was added Pd/C (10%, 2.4 g) under argon. Methanol (100 ml) wasadded via syringe, and H₂ gas was introduced and the mixture stirredvigorously under an atmosphere of H₂. After 48 h, the mixture wasflushed with nitrogen, filtered through celite and concentrated toafford a mixture of starting material and N,N-dimethylpiperidin-4-aminedihydrochloride as a white solid. This solid was treated with1-Fluoro-2-nitro-4-trifluoromethyl-benzene (3.2 ml, 22.9 mmol),triethylamine (12.7 ml, 92 mmol), and 50 ml dry THF. The mixture washeated to 75° C. with a water-cooled reflux condenser for 12 h. Themixture was allowed to cool to ambient temperature, was filtered througha fritted funnel, and concentrated to an orange oil. The residue waspurified by silica gel chromatography (MC/MeOH/conc. NH₄OH) to give thedesired product as an orange oil. MS (m/z): 318.1 (M+H)⁺. Calc'd forC₁₄H₁₈F₃N₃O₂: 317.31.

Step 3:1-(2-amino-4-(trifluoromethyl)phenyl)-N,N-dimethylpiperidin-4-amine

To N,N-dimethyl-1-(2-nitro-4-(trifluoromethyl)phenyl)piperidin-4-amine(3.4 g, 11 mmol) was added Pd/C (10%, 0.57 g) under nitrogen. Methanol(25 mL) was added via syringe, and H₂ gas was introduced and the mixturestirred vigorously under an atmosphere of H₂. After 96 h, the mixturewas flushed with nitrogen, filtered through celite and concentrated. Theresidue was resubjected to the reaction conditions. After 12 h, thereaction was flushed with nitrogen, filtered through celite andconcentrated. The resulting solid was triturated with methanol ten timesto give the title compound as a pink solid. MS (m/z): 288.2 (M+H)⁺.Calc'd for C₁₄H₂₀F₃N₃: 287.32.

Example 125

Synthesis of(S)-1-(2-amino-4-(trifluoromethyl)phenyl)-N,N-dimethylpiperidin-3-amineStep 1:(S)-N,N-dimethyl-1-(2-nitro-4-(trifluoromethyl)phenyl)piperidin-3-amine

To a light yellow solution of (S)-tert-butyl3-aminopiperidine-1-carboxylate (0.52 g, 2.6 mmol) in 25 ml MeOH wasadded sodium cyanoborohydride (0.33 g, 5.2 mmol), AcOH (0.74 ml, 13mmol), and formaldehyde (37 wt. % solution in water, 1.0 ml). Afterstirring approximately 12 h, the reaction was quenched by the additionof 5 ml saturated aqueous sodium bicarbonate. The volatile organicsolvents were removed in vacuo, and water and EtOAc was added. Theorganic layer was removed, and the aqueous layer was extracted twicewith EtOAc. The combined organic layers were dried with Na₂SO₄,filtered, and concentrated to give a yellow oil. The resulting materialwas treated with 4 ml 4N HCl in dioxane at 0° C. After 2 h, the solutionwas concentrated in vacuo to give a light yellow solid. This solid wastreated with 1-Fluoro-2-nitro-4-trifluoromethylbenzene (0.37 ml, 2.6mmol), sodium bicarbonate (1.0 g, 13 mmol), and 5 ml dry THF. Themixture was heated to 75° C. with a water-cooled reflux condenser for 12h. The mixture was allowed to cool to ambient temperature, was filteredthrough a fritted funnel, and concentrated to give the desired productas an orange oil. MS (m/z): 318.0 (M+H)⁺. Calc'd for C₁₄H₁₈F₃N₃O₂:317.31.

Step 2:(S)-1-(2-amino-4-(trifluoromethyl)phenyl)-N,N-dimethylpiperidin-3-amine

(S)-N,N-Dimethyl-1-(2-nitro-4-(trifluoromethyl)phenyl)piperidin-3-amine(0.82 g, 2.6 mmol) was reduced with Pd/C (10%, 0.27 g) in 10 ml methanolin a manner similar to Example 124-Step 3 to give the title compound asan orange-red oil. MS (m/z): 288.2 (M+H)⁺. Calc'd for C₁₄H₂₀F₃N₃:287.32.

Example 126

Synthesis of 2-(1-methylpiperidin-3-yl)-5-(trifluoromethyl)benzenamineStep 1: 3-(2-nitro-4-(trifluoromethyl)phenyl)pyridine

A mixture of pyridin-3-ylboronic acid (0.99 g, 8.1 mmol),2-bromo-5-(trifluoromethyl)benzenamine (1.2 ml, 8.1 mmol),tetrakis(triphenylphosphine)palladium (0.28 g, 0.24 mmol), sodiumcarbonate (2.0 M solution in water, 8.0 ml, 16 mmol), 4 ml ethanol, and20 ml toluene was heated to 90° C. under nitrogen with a water-cooledreflux condenser. After 12 h, mixture was cooled to ambient temperature,and was partitioned between EtOAc and 1N NaOH. The organic layer waswashed once with brine, dried with Na₂SO₄, filtered, and concentrated togive a brown oil, which was further purified by silica gelchromatography (EtOAc/hexanes) to give the desired product as a waxyorange solid. MS (m/z): 269.0 (M+H)⁺. Calc'd for C₁₂H₇F₃N₂O₂: 268.19.

Step 2: 2-(1-methylpiperidin-3-yl)-5-(trifluoromethyl)benzenamine

To an orange solution of 3-(2-nitro-4-(trifluoromethyl)phenyl)pyridine(1.4 g, 5.2 mmol) in 2 ml acetone and 1 mL benzene was added iodomethane(1.0 ml, 16 mmol). The solution was allowed to stand for 5 days, and wasconcentrated in vacuo to give an orange solid. A portion of thismaterial was treated with platinum (IV) oxide (0.11 g, 0.49 mmol) in 5ml MeOH under an atmosphere of hydrogen for approximately 24 h. Thereaction was flushed with nitrogen, filtered through celite, andconcentrated. Purification by silica gel chromatography (MC/MeOH/conc.NH₄OH) provided the title compound. MS (m/z): 259.0 (M+H)⁺. Calc'd forC₁₃H₁₇F₃N₂: 258.28.

Example 127

Synthesis of 2-(2-(dimethylamino)ethyl)-5-(trifluoromethyl)benzenamine

The title compound was synthesized in a manner similar to that describedin Example 58 of pending U.S. Patent Application No. 60/569,193. MS(m/z): 233.1 (M+H)⁺. Calc'd for C₁₁H₁₅F₃N₂: 232.25.

Example 128

Synthesis of N1,N1-dimethyl-4-(trifluoromethyl)benzene-1,2-diamine

The title compound was synthesized in a manner similar to Example 55 ofpending U.S. Patent Application No. 60/569,193. MS (m/z): 205.1 (M+H)⁺.Calc'd for C₉H₁₁F₃N₂: 204.19.

Example 129

Synthesis of(S)-3-((1-methylpyrrolidin-2-yl)methoxy)-5-(trifluoromethyl)benzenamine

The title compound was synthesized by a method similar to that describedin WO 2002066470 A1.

Example 130

Synthesis of4-bromo-N-1-(3-(dimethylamino)propyl)-N1-methylbenzene-1,2-diamine

To N-(4-Bromo-2-nitro-phenyl)-N,N′,N′-trimethylpropane-1,3-diamine (madeby a method similar to that of Example 103—Step 1) (0.54 g, 1.7 mmol) in20 ml EtOH was added SnCl₂ (0.51 g, 2.67 mmol). The mixture was sealedand was heated to 80° C. for 12 h. An additional amount of SnCl₂ (0.51g, 2.67 mmol) was added and heating continued for 12 h. The reaction wascooled to ambient temperature, and was poured into a mixture of EtOAcand saturated aqueous sodium bicarbonate. The mixture was filteredthrough celite, and the organic layer was removed. The aqueous layer wasextracted twice with EtOAc, and the combined organic layers were driedwith Na₂SO₄, filtered, and concentrated to give a cloudy oil. Thismaterial was filtered through silica gel with 90/10/1dichloromethane/MeOH/conc. NH₄OH and concentrated in vacuo to give thetitle compound as a red oil. MS (ES⁺): 285.9 (M+H)⁺. Calc'd forC₁₂H₂₀BrN₃: 286.21.

Examples 131-141 were prepared by methods similar to the proceduresdescribed in pending U.S. Patent Application No. 60/569,193.

Example No Structure 131

132

133

134

135

136

137

138

139

140

141

Example 142

1-(6-amino-3,3-dimethylindolin-1-yl)ethanone

The title compound was prepared according to a procedure described inU.S. Patent Publication No. 2003/0203922.

Example 143

4-(1-methylpiperidin-4-yloxy)-3-(trifluoromethyl)benzenamine

The title compound was synthesized in a manner similar to Example 56 ofpending U.S. Patent Application No. 60/569,193.

Example 144

4-(3-(diethylamino)propoxy)-3-(trifluoromethyl)benzenamine

The title compound was synthesized in a manner similar to Example 143above.

Example 145

4-methoxy-2,3-dimethylbenzenamine

The title compound was synthesized in a manner similar to Example 143above.

Example 146

1-methyl-1H-indol-4-amine

The title compound was synthesized in a manner similar to Example 143above.

Example 147

1-(4-amino-2-(trifluoromethyl)phenyl)-3-(2-morpholinoethyl)urea Step 1:1-(2-morpholinoethyl)-3-(4-nitro-2-(trifluoromethyl)phenyl)urea

To a solution of 1-isocyanato-4-nitro-2-(trifluoromethyl)benzene (339μL, 2.21 mmol, 1.0 equiv) in benzene (3.0 mL), was added2-morpholinoethanamine (316 mg, 2.43 mmol, 1.0 equiv). The resultingprecipitant was filtered and washed with hexanes to provide1-(2-morpholinoethyl)-3-(4-nitro-2-(trifluoromethyl)phenyl)urea, whichwas advanced without further purification. MS (MH⁺) 363; Calculated forC₁₄H₁₇F₃N₄O₄: 362.1

Step 2: 1-(4-amino-2-(trifluoromethyl)phenyl)-3-(2-morpholinoethyl)urea

A mixture of1-(2-morpholinoethyl)-3-(4-nitro-2-(trifluoromethyl)phenyl)urea (651 mg,1.80 mmol, 1.0 equiv) and 10% Pd/C (20 mg) in EtOAc (25 mL) and MeOH (2mL) was exposed to an atmosphere of H₂ (balloon). Upon completion of thereduction, the reaction mixture was filtered through celite andconcentrated in vacuo to afford1-(4-amino-2-(trifluoromethyl)phenyl)-3-(2-morpholinoethyl)urea, whichwas advanced without further purification. MS m/z: 333 (M+H⁺);Calculated for C₁₄H₁₉F₃N₄O₂: 332.2

Example 148

3-amino-N-(2-morpholinoethyl)-5-(trifluoromethyl)benzamide Step 1:N-(2-morpholinoethyl)-3-nitro-5-(trifluoromethyl)benzamide

A mixture of 3-nitro-5-(trifluoromethyl)benzoic acid (300 mg, 1.29 mmol,1.0 equiv) and thionyl chloride (2.0 ml) was heated at 75° C. for 1 h.The solvent was removed in vacuo and the residue taken up in CH₂Cl₂ (5.0ml). To the solution was added 2-morpholinoethanamine (185 mg, 1.42mmol, 1.1 equiv) and triethylamine (0.54 ml, 3.86 mmol, 3.0 equiv).After the reaction was complete, the solution was diluted with CH₂Cl₂(ca. 10 ml) and washed with water and brine. After drying with Na₂SO₄and concentration in vacuo, the resultingN-(2-morpholinoethyl)-3-nitro-5-(trifluoromethyl)benzamide was advancedwithout further purification. MS m/z: 348 (M+H⁺); Calculated forC₁₄H₁₆F₃N₃O₄: 347.1

Step 2: 3-amino-N-(2-morpholinoethyl)-5-(trifluoromethyl)benzamide

A mixture of N-(2-morpholinoethyl)-3-nitro-5-(trifluoromethyl)benzamide(300 mg, 0.865 mmol, 1.0 equiv) and 10% Pd/C (20 mg) in EtOAc (25 ml)and MeOH (2 mL) was exposed to an atmosphere of H₂ (balloon). Uponcompletion of the reduction, the reaction mixture was filtered throughcelite and concentrated in vacuo to afford3-amino-N-(2-morpholinoethyl)-5-(trifluoromethyl)benzamide, which wasadvanced without further purification. MS m/z: 318 (M+H⁺); Calculatedfor C₁₄H₁₈F₃N₃O₂: 317.1

Example 149

4-chloro-N1-(3-(dimethylamino)propyl)-N1-methylbenzene-1,2-diamine Step1: Preparation of4-chloro-N-(3-(dimethylamino)propyl)-N-methyl-2-nitrobenzenamine

To 2,5-dichloronitrobenzene (3.0 g, 16 mmol) was addedN1,N1,N3-trimethylpropane-1,3-diamine (2.2 g, 19 mmol). The mixture wasstirred for 2.5 days at RT, diluted with 0.01 N HCl and extracted withEtOAc. The aqueous layer was made basic with Na₂CO₃ and extracted withEtOAc. The organic layer was dried over anhydrous Na₂SO₄, filtered andconcentrated to yield4-chloro-N-(3-(dimethylamino)propyl)-N-methyl-2-nitrobenzenamine as anorange oil. MS m/z=272 [M+H]⁺. Calc'd for C₁₂H₁₈ClN₃O₂: 271.75.

Step 2: Preparation of4-chloro-N1-(3-(dimethylamino)propyl)-N-1-methylbenzene-1,2-diamine

To 4-chloro-N-(3-(dimethylamino)propyl)-N-methyl-2-nitrobenzenamine (4.0g, 15 mmol) in EtOH (80 ml) and water (10 ml) was added Raney-Ni (10 g).The mixture was stirred for 5 hours at RT, filtered through a pad ofCelite and concentrated to yield4-chloro-N1-(3-(dimethylamino)propyl)-N1-methylbenzene-1,2-diamine as adeep red oil. MS m/z=242 [M+H⁺. Calc'd for C₁₂H₂₀ClN₃: 241.77.

Example 150 3-amino-4-deuteromethoxy(-d₃)benzotrifluoride

Step 1: To 10 g of deuterated methanol over an ice bath was added sodiummetal until a cloudy solution formed. 4-Chloro-3-nitrobenzotrifluoride(2.25 g, 1.46 mL, 0.01 mol), was added to the solution dropwise over anice bath. The reaction mixture was allowed to stir 24 hours at roomtemperature. The orange solution is brought to pH 6 (turns yellow) withacetic acid added dropwise over an ice bath.Step 2: 10% Palladium on carbon (0.05 g) was added to a reaction mixtureof the nitroaniline (0.01 mol) allowed to stir at room temperature undera H₂(g) atmosphere (via balloon). The reaction mixture was then filteredthrough celite. The filtrate was concentrated to afford a yellow oilthat was reconstituted in dichloromethane (5 ml) and purified by flashsilica column using isocratic 90/10/1 CH₂Cl₂/CH₃OH/NH₄OH. A very paleyellow solid is isolated. LC-MS(+) revealed a mass of 195 (M+H⁺); calc'dfor C₈H₅D₃F₃NO: 194.17.

Example 151

3-amino-4-ethoxybenzotrifluoride

The title compound was prepared by a method similar to Example 150,using ethanol in place of deuteromethanol and purified by flash silicacolumn using isocratic 90/10/1: CH₂Cl₂/CH₃OH/NH₄OH. A very pale yellowsolid was isolated. LC-MS(+) revealed a mass of 206 (M+H⁺); calc'd forC₉H₁₀F₃NO: 205.18.

Example 152

4-cyclopropyl-N1-(3-(dimethylamino)propyl)-N1-methylbenzene-1,2-diamineStep 1: N-(4-Bromo-2-nitro-phenyl)-N,N′,N′-trimethylpropane-1,3-diamine

To a round bottom flask at 0° C. was added4-Bromo-1-fluoro-2-nitrobenzene (10 g, 45.46 mmol) andN,N,N′-Trimethyl-propane-1,3-diamine (6.99 ml, 47.73 mmol). The reactionwas allowed to warm to RT and stirred for 16 h. The reaction wasextracted into EtOAc, washed once with saturated aqueous NaHCO₃, twicewith water, and then dried over Mg₂SO₄. The organic layer was filteredand concentrated to yield the title compound as a bright orange solid.

MS (M+H⁺)=316, 318; Calc'd for C₁₂H₁₈BrN₃O₂=316.19.

Step 2:4-cyclopropyl-N-(3-(dimethylamino)propyl)-N-methyl-2-nitrobenzenamine

To a pressure vessel was added2-cyclopropyl-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (900 mg, 5.36mmol), potassium phosphate (3.0 g, 14.42 mmol), and 0.82 mL water. Afterstirring at RT for 15 minutes,N-(4-Bromo-2-nitro-phenyl)-N,N′,N′-trimethyl-propane-1,3-diamine (Step1, 1.30 g, 4.12 mmol), palladium acetate (92 mg, 0.412 mmol),tricyclohexylphosphine (231 mg 0.824 mmol), and 21 ml toluene wereadded. The reaction was sealed and stirred at 80° C. for 19 h. Thereaction was then cooled to RT, quenched with EtOAc and extracted intowater, washed once with brine, and then dried over Mg₂SO₄. The crudemixture was then purified by reverse phase chromatography to yield thetitle compound as a dark red-brown oil. MS (M+H⁺)=278; Calc'd forC₁₅H₂₃N₃O₂=277.36.

Step 3:4-cyclopropyl-N-1-(3-(dimethylamino)propyl)-N-1-methylbenzene-1,2-diamine

4-cyclopropyl-N-(3-(dimethylamino)propyl)-N-methyl-2-nitrobenzenamine(Step 2, 600 mg, 2.16 mmol) was dissolved in 22 mL MeOH. Palladium (115mg, 0.108 mmol, 10% w/w on carbon) was added, a balloon containinghydrogen was inserted, and the reaction was stirred at RT for 18 h. Thesolution was then filtered through a pad of Celite and concentrated,yielding the title compound as viscous red-brown oil. MS (M+H⁺)=248;Calc'd for C₁₅H₂₅N₃=247.38.

Example 153

4-(3-Piperidin-1-yl-propoxy)aniline Step 1: 1-(3-Chloropropyl)piperidine

A mixture of 1-bromo-3-chloropropane (65.6 g, 0.417 mol) and piperidine(62 ml, 0.625 mol) in anhydrous THF (200 ml) was heated to reflux for 24h. The mixture was cooled to RT and filtered to remove solids. Theorganics were concentrated under in vacuo. The resultant residue wastaken up in 2N HCl and washed twice with ethyl acetate. The aqueouslayer was basicified with 2N NaOH to pH 14. The compound was extractedthree times with ethyl acetate and the combined organics dried overanhydrous magnesium sulfate. The solution was then concentrated underreduced pressure to give the desired compound as a yellowish oil.

Step 2: 1-[3-(4-nitrophenoxy)propyl]piperidine

In a three-necked flask fitted with an overhead mechanical stirrer, amixture of 1-(3-chloropropyl)piperidine (49.8 g, 0.308 mol),4-nitrophenol (42.8 g, 0.308 mol) and potassium carbonate (212 g, 1.53mol), in anhydrous DMF (200 mL) was heated to 94° C. and stirred for 18h. The mixture was cooled to room temperature, then diluted with 2 Lwater. The organics were taken up in ethyl acetate and washed twice with2N sodium hydroxide and then brine. The combined organics were driedover magnesium sulfate then concentrated under reduced pressure to givethe title compound as a yellowish oil.

Step 3: 4-(3-Piperidin-1-ylpropoxy)aniline

A mixture of 1-[3-(4-nitrophenoxy)propyl]piperidine (15.5 g, 58.6 mmol)and 10% Pd/C (12.5 g) in 150 mL of EtOH was placed under a balloon ofH₂. The mixture was stirred for 18 h. The catalyst was removed bysuction filtration and the organics concentrated to give the titlecompound as a yellowish oil. MS (m/z)=235.2 (M+H⁺); Calc'd forC₁₄H₂₂N₂O=234.34.

Example 154

4-(3-(dimethylamino)propoxy)aniline Step 1:1-(3-chloropropoxy)-4-nitrobenzene

A solution of 4-Nitrophenol (10 g, 72 mmol) dissolved in acetonitrile(100 ml was charged with potassium carbonate (24.9 g, 180 mmol) and1-bromo-3-chloropropane (113.2 g, 720 mmol). The mixture was heated andstirred at reflux overnight. The reaction was cooled to roomtemperature, the solids filtered off and the solvent evaporated underreduced pressure to give the title compound.

Step 2: 4-(3-(dimethylamino)propoxy)nitrobenzene

A mixture of 1-(3-chloropropoxy)-4-nitrobenzene (2 g, 9.27 mmol),potassium carbonate (7.69 g, 46.4 mmol) and acetonitrile (15 ml) wasprepared and stirred in a tube. To the stirring solution dimethylaminehydrochloride (3.78 g, 46.4 mmol) was added quickly. The tube was sealedand the mixture was stirred while heating overnight at 80° C. Themixture was cooled well before opening the pressure tube, then water anddichloromethane were added and the aqueous layer was extracted withdichloromethane. The combined organics were dried and evaporated givingthe title product.

Step 3: 4-(3-(dimethylamino)propoxy)aniline

4-(3-(dimethylamino)propoxy)nitrobenzene (4.4 g, 19.6 mmol) washydrogenated over Pd (10% on C, 0.4 g) in ethanol (50 ml) for 16 h. Thecatalyst was filtered off and the solvent removed under reduced pressureto afford the title compound as a brown oil. MS (m/z)=195.3 (M+H⁺);Calc'd for C₁₁H₁₈N₂O=194.28.

Example 155

3-(3-Piperidin-1-yl-propoxy)aniline

The title compound was prepared by a method similar to that described inExample 154 above, wherein 3-nitrophenol was substituted for4-nitrophenol in Step 1 and piperidine for dimethylamine hydrochloridein Step 2. MS (m/z)=235.2 (M+H⁺); Calc'd for C₁₄H₂₃N₂O=234.34.

Example 156

5-(2-(diethylamino)ethoxy)-2-methoxyaniline

Step 1: 4-Methoxyphenylacetate

4-Methoxyphenol (2 g, 16 mmol) was dissolved in anhydrous pyridine (6.5ml) and stirred while cooling at 0° C. under a nitrogen atmosphere.Acetic anhydride (7.5 ml, 80 mmol) was added. The reaction was allowedto warm to room temperature, where it was stirred for 16 h. The reactionwas cooled in an ice bath before quenching with ice. The solution wasneutralized with saturated aqueous sodium bicarbonate solution and thenextracted with ethyl acetate. The combined organic extracts were washedtwice with 2M HCl, then with saturated aqueous copper sulfate solutionto remove residual pyridine. The organic extract was further washed with5M aqueous sodium hydroxide solution and brine, then dried over sodiumsulfate and concentrated under reduced pressure to afford a clear oil,which crystallized to give the title compound as a white solid.

Step 2: 4-Methoxy-3-nitrophenylacetate

4-Methoxyphenylacetate (2.37 g, 14.3 mmol) was dissolved in glacialacetic acid (4 ml) and cooled to 5-10° C. A chilled mixture of glacialacetic acid (1.3 ml), fuming nitric acid (0.9 ml) and acetic anhydride(1.3 ml) was added dropwise as the temperature gradually increased to25° C. The reaction was stirred for 1 h, then quenched with ice anddiluted with water. The resulting precipitate was isolated byfiltration, rinsed with water and dried in vacuo to afford the titlecompound as a fine crystalline yellow solid.

Step 3: 4-Methoxy-3-nitrophenol

4-Methoxy-3-nitrophenylacetate (2.46 g, 11.7 mmol) was dissolved inanhydrous ethanol (80 ml) and sodium ethoxide (1.19 g, 17.5 mmol) wasadded. The reaction was stirred at room temperature for 0.5 h. The darkred solution was acidified with 2M HCl and concentrated under reducedpressure. The residue was taken up into water and extracted withdichloromethane. The combined organics were washed with 2M HCl andbrine, then dried over sodium sulfate. Evaporation of the solvent underreduced pressure gave the title compound as a yellow solid.

Step 4: 4-(2-chloroethoxy)-1-methoxy-2-nitrobenzene

4-Methoxy-3-nitrophenol (0.8 g, 4.7 mmol) was dissolved in acetonitrile(13 ml). Potassium carbonate (1.63 g, 11.8 mmol) was added, followed by1-bromo-2-chloroethane (3.93 ml, 47.2 mmol). The reaction was heated andstirred at reflux for 20 h. The reaction was cooled to room temperature,the solid was then filtered off and the solvent evaporated under reducedpressure to give the title compound.

Step 5: N,N-Diethyl-2-(4-methoxy-3-nitrophenoxy)ethylamine

4-(2-chloroethoxy)-1-methoxy-2-nitrobenzene (0.15 g, 0.67 mmol) wasdissolved in acetonitrile (1 ml). Excess diethylamine (1.5 ml, 17.7mmol) was added and the reaction heated in the microwave (T=120° C., 40min) to complete conversion. The reaction mixture was diluted withdichloromethane, then washed with 5M sodium hydroxide and brine, thendried over sodium sulfate. Evaporation of the solvent under reducedpressure gave the title compound as an orange oil.

Step 6: 5-(2-(diethylamino)ethoxy)-2-methoxyphenylamine

N,N-diethyl-2-(4-methoxy-3-nitrophenoxy)ethylamine (0.29 g, 1.1 mmol)was hydrogenated over Pd (5% on C, 50% wet, 0.12 g) in ethanol (5 ml)for 16 hours. The catalyst was filtered off and the solvent removedunder reduced pressure to afford the title compound as a red oil. MS(m/z)=239(M+H⁺); Calc'd for C₁₃H₂₂N₂O₂=238.33.

Example 157

4-(2-(diethylamino)ethoxy)-2-methoxyaniline Step 1:4-Fluoro-2-methoxynitrobenzene

5-Fluoro-2-nitrophenol (6 g, 38.2 mmol) was dissolved in anhydrous DMF(20 ml). Potassium carbonate (5.3 g, 38.2 mmol) was added, followed byiodomethane (2.28 ml, 38.2 mmol). The reaction was stirred at roomtemperature for 16 h, then partitioned between dichloromethane andwater. The organic layer was washed three times with 1M sodium hydroxideand once with brine, then dried over sodium sulfate. Removal of thesolvent in vacuo afforded the title compound as a yellow oil, whichsolidified upon standing.

Step 2: 3-Methoxy-4-nitrophenol

4-Fluoro-2-methoxynitrobenzene (4.68 g, 27.4 mmol) was suspended in a 5Mpotassium hydroxide solution (50 ml) and heated to 90° C. for 5 h. Thered solution was cooled to room temperature and acidified to pH 6 with1M HCl. The aqueous solution was extracted three times with ethylacetate and the combined organics were washed with brine and dried oversodium sulfate. Removal of the solvent under reduced pressure, followedby purification by flash column chromatography (1:1 hexane/ethylacetate) afforded the title compound as a yellow solid.

Step 3: 4-(2-chloroethoxy)-2-methoxy-1-nitrobenzene

3-Methoxy-4-nitrophenol (0.6 g, 3.6 mmol) was dissolved in acetonitrile(15 ml). Potassium carbonate (1.3 g, 9.1 mmol) was added, followed by1-bromo-2-chloroethane (5.1 g, 35.5 mmol). The reaction was stirred in asealed pressure tube at 80° C. for 20 h. The reaction was cooled to roomtemperature, the solid was then filtered off and the solvent evaporatedunder reduced pressure. The residue was then taken up into ethyl acetateand washed with 1M sodium hydroxide, brine, and then dried over sodiumsulfate. Evaporation of the solvent afforded the title compound as ayellow solid.

Step 4: N,N-Diethyl-2-(3-methoxy-4-nitrophenoxy)ethylamine

4-(2-Chloroethoxy)-2-methoxy-1-nitrobenzene (0.22 g, 0.9 mmol) wasdissolved in acetonitrile (1 ml). Diethylamine (0.14 ml, 2.6 mmol) andpotassium carbonate (0.31 g, 2.2 mmol) were added and the reaction washeated in a sealed pressure tube to 80° C. for 20 h. The reactionmixture was diluted with dichloromethane, then washed with 1M sodiumhydroxide and brine, then dried over sodium sulfate. Evaporation of thesolvent under reduced pressure gave the title compound as a brown oil.

Step 5: N,N-Diethyl-2-(4-amino-3-methoxyphenoxy)ethylamine

N,N-Diethyl-2-(3-methoxy-4-nitrophenoxy)ethylamine (140 mg, 0.5 mmol)was hydrogenated over Pd (5% on C, 50% wet, 40 mg) in ethanol (5 ml) for16 hours. The catalyst was filtered off and the solvent removed underreduced pressure to afford the title compound as a brown oil. MS(m/z)=239 (M+H⁺); Calc'd for C₁₃H₂₂N₂O₂=238.33

Example 158

N-(5-amino-2-tert-butylphenyl)-2-dimethylamino)acetamide Step 1:2-tert-butyl-5-nitrobenzenamine

Concentrated sulfuric acid (1 L) was cooled to −10° C. with a dryice-isopropanol bath in a 2 L 3-necked round bottom flask fitted with amechanical stirrer and temperature probe. The 2-t-butylaniline (109 g,730 mmol) was added, giving a clumpy solid. Once the temperature of themixture was stabilized at −10° C., the potassium nitrate (101 g, 1001mmol) was added portion wise, as a solid, over a 4-hour period,maintaining the temperature between −20 and −5° C. Once all of thepotassium nitrate was added, the reaction was left to stir overnightwith gradual warming to room temperature. The reaction was quenched bydiluting with water and then extracting three times with EtOAc. Each ofthe EtOAc extracts was washed multiple times with saturated NaHCO₃,until gas evolution ceased, and with brine. The ethyl acetate extractswere combined, dried over anhydrous Na₂SO₄, filtered and concentratedunder reduced pressure giving a black oil. The oil was eluted through a36 x & cm column of silica gel with EtOAc: hexanes gradient 5-50%.Solvent evaporation afforded 2-tert-butyl-5-nitrobenzenamine as a redsolid.

Step 2: 2-bromo-N-(2-tert-butyl-5-nitrophenyl)acetamide

2-tert-Butyl-5-nitrobenzenamine (70 g, 359 mmol) and a catalytic amountof DMAP were dissolved into THF (1.5 L) under N₂. Triethylamine (109 g,1077 mmol) was added and the solution was cooled to 0° C. Bromoacetylbromide (207 g, 1023 mmol) was then added and the reaction was stirredat room temperature for 16 hours. The reaction was then partiallyconcentrated under reduced pressure, treated with water, and extractedthree times with EtOAc. The EtOAc extracts were washed with brine,combined, dried over Na₂SO4 and concentrated to a black oil. The oil waspurified using silica chromatography, 95:5:0.5 CH₂Cl₂:MeOH:NH₄OH, giving2-bromo-N-(2-tert-butyl-5-nitrophenyl)acetamide as a brown solid.

Step 3: N-(2-tert-butyl-5-nitrophenyl)-2-(dimethylamino)acetamide

2-Bromo-N-(2-tert-butyl-5-nitrophenyl)acetamide (80 g, 253, mmol) andpotassium carbonate (70 g, 506 mmol) were combined in THF (1.75 L), andthe mixture was cooled to 0° C. N,N-Dimethylamine (40 mL of a 2 Msolution in THF, 800 mmol) was then added to the mixture through anaddition funnel over a 30-minute period. The mixture was then stirred atroom temperature for 16 hours. The mixture was filtered and the filtrateconcentrated. The crude material was purified by silica chromatographyeluting with 50% EtOAc:hexanes to giveN-(2-tert-butyl-5-nitrophenyl)-2-(dimethylamino)acetamide as a brownsolid.

Step 4: N-(5-amino-2-tert-butylphenyl)-2-dimethylamino)acetamide

To a solution ofN-(2-tert-butyl-5-nitrophenyl)-2-(dimethylamino)acetamide (25.8 g, O₂mmol) in 1,4-dioxane (200 mL) was added 10% Pd/C (2.5 g) as a slurry ina minimal amount of EtOH. The mixture was evacuated and purged with H₂,and stirred at room temperature for 16 hours. The reaction was thenpurged with N₂ and filtered through celite. The filtrate wasconcentrated and purified using silica chromatography, 97.5:2.5:0.25 to95:5:0.5 CH₂Cl₂:MeOH:NH₄OH, to affordN-(5-amino-2-tert-butylphenyl)-2-dimethylamino)acetamide as a brownsolid.

Example 159

3-((dimethylamino)methyl)-5-(trifluoromethyl)benzenamine

The title compound was synthesized using a procedure similar to thatdescribed in Example 95. MS m/z=219 [M+H]⁺. Calc'd for C₁₀H₁₃F₃N₂: 218.

Example 160

3-(pyrrolidin-1-ylmethyl)-5-(trifluoromethyl)benzenamine

The title compound was synthesized using a procedure similar to thatdescribed in Example 95. MS m/z=245 [M+H]⁺. Calc'd for C₁₂H₁₅F₃N₂: 244.

Example 161

3-(pyrrolidin-1-ylmethyl)-5-(trifluoromethyl)benzenamine

The title compound was synthesized using a procedure similar to thatdescribed in Example 95. MS m/z=261 [M+H]⁺. Calc'd for C₁₂H₁₅F₃N₂O: 260.

Example 162

1-(2-amino-4-(trifluoromethyl)phenyl)pyrrolidin-2-one

A resealable tube was charged with 2-bromo-5-(trifluoromethyl)aniline(1.00 g, 4.16 mmol), 2-pyrrolidinone (0.425 g, 5.00 mmol), N,N′-ethylenediamine (0.037 g, 0.42 mmol), potassium carbonate (1.15 g, 8.32 mmol),copper iodide (0.80 mg, 0.42 mmol) and toluene (1.0 mL). The tube wassealed and the mixture was heated at 80° C. for 24 h. The resultingmixture was partitioned between ethyl acetate and water. The organicphase was separated, dried over anhydrous sodium sulfate, filtered, andconcentrated. The residue was purified via column chromatography onsilica gel (gradient elution with 0-100% ethyl acetate-hexane) to afford1-(2-amino-4-(trifluoromethyl)phenyl)pyrrolidin-2-one as a gray solid.MS m/z=245 [M+H]⁺. Calc'd for C₁₁H₁₁F₃N₂O: 244.

Example 163

3-(2-amino-4-(trifluoromethyl)phenyl)oxazolidin-2-one

The title compound was synthesized using a procedure similar to thatdescribed in Example 162. MS m/z=247 [M+H]⁺. Calc'd for C₁₀H₉F₃N₂O₂:246.

Example 164

3-(3-(4-methylpiperazin-1-yl)propyl)-5-(trifluoromethyl)benzenamine

A solution of 1-allyl-4-methylpiperazine (2.12 g, 14.0 mmol) and 9-BBN(0.5 M in THF, 1.7 g, 28 mL, 14.0 mmol) was heated at reflux for 3 h andthen cooled to RT. The solution was added to a mixture of3-bromo-5-(trifluoromethyl)aniline (3.0 o g, 12.5 mmol), potassiumcarbonate (8.64 g, 62.5 mmol), PdCl₂(PPh₃)₂—CH₂Cl₂ adduct (0.457 g, 0.6mmol), DMF (30 mL) and water (2 mL). The mixtre was heated to 75° C. for24. The mixture was concentrated, triturated with dichloromethane, andfiltered. The filtrate was concentrated and the residue was purified viacolumn chromatography on silica gel (gradient elution with 0-20%methanol-dichloromethane) to afford3-(3-(4-methylpiperazin-1-yl)propyl)-5-(trifluoromethyl)benzenamine as abrown oil. MS m/z=302 [M+H]⁺. Calc'd for C₁₅H₂₂F₃N₃: 301.

Example 165

3-(3-morpholinopropyl)-5-(trifluoromethyl)benzenamine

The title compound was synthesized using a procedure similar to thatdescribed in Example 164. MS m/z=289 [M+H]⁺. Calc'd for C₁₄H₁₉F₃N₂O:288.

Example 166

2-(3-dimethylamino-1-propynyl)-5-(trifluoromethyl)aniline

A resealable tube was charged with 2-bromo-5-(trifluoromethyl)aniline(1.00 g, 4.16 mmol), 1-dimethylamino-2-propyne (0.520 g, 6.20 mmol),PdCl₂(PPh₃)₂ (0.15 g, 0.21 mmol), copper iodide (0.80 mg, 0.42 mmol),diisopropylethylamine (1.0 mL) and acetonitrile (3.0 mL). The system waspurged with argon, the tube sealed and the mixture stirred at roomtemperature for 20 h. The reaction mixture was filtered through celiteand concentrated. The residue was purified via column chromatography onsilica gel (gradient elution with 0-10% methanol-dichloromethane) toafford 2-(3-dimethylamino-1-propynyl)-5-(trifluoromethyl)aniline as abrown oil. MS m/z=243 [M+H]⁺. Calc'd for C₁₂H₁₃F₃N₂: 242.

Example 167

(S)-1-(2-amino-4-(trifluoromethyl)phenyl)-N,N-dimethylpiperidin-3-amineStep 1: (S)-tert-butyl1-(2-nitro-4-(trifluoromethyl)phenyl)piperidin-3-ylcarbamate

To a 200-mL RBF was added (s)-3-n-boc-amino piperidine (10.9 g, 54.4mmol), Sodium bicarbonate (11.4 g, 136 mmol), THF, and1-fluoro-2-nitro-4-(trifluoromethyl)benzene (7.62 ml, 54.4 mmol). Theyellow mixture was heated to 70° C. with a water-cooled refluxcondenser. The orange mixture was allowed to stir for 14 h, and was thencooled to ambient temperature, and filtered through a glass frit,rinsing with EtOAc. Concentration in vacuo afforded an orange oil, whichcrystallized on standing to an orange solid. The material was treatedwith 250 mL hexanes and heated on the rotovap (no vacuum) to 60° C.Small amounts of EtOAc were added until all solid dissolved, totalvolume of EtOAc was approx 10 mL. The solution was allowed to coolovernight, resulting in the formation of orange crystals. The liquid wasdecanted and the crystals rinsed twice with 50 mL hexanes. The crystalswere collected to give (S)-tert-butyl1-(2-nitro-4-(trifluoromethyl)phenyl)piperidin-3-ylcarbamate as orangecrystals. The filtrate was concentrated to an orange solid. Thismaterial was treated with 150 mL hexanes and was heated to 65° C. Almostall of the material had dissolved. The hot liquid was decanted into aflask and allowed to cool overnight, resulting in an orange solid. Theliquid was discarded, and additional crystals of (S)-tert-butyl1-(2-nitro-4-(trifluoromethyl)phenyl)piperidin-3-ylcarbamate werecollected. MS m/z=390 [M+H]⁺. Calc'd for C₁₇H₂₀F₃N₃: 389.

Step 2: (S)-1-(2-nitro-4-(trifluoromethyl)phenyl)piperidin-3-aminedihydrochloride

A solution of (S)-tert-butyl1-(2-nitro-4-(trifluoromethyl)phenyl)piperidin-3-ylcarbamate (15.64 g,40 mmol) was cooled to 7° C. and hydrochloric acid 4.0 M dioxane (80 ml,321 mmol) was added and the mixture allowed to warm to ambienttemperature. The orange solution was allowed to stir for 14 h, at whichpoint it was concentrated in vacuo to give(S)-1-(2-nitro-4-(trifluoromethyl)phenyl)piperidin-3-aminedihydrochloride as a yellow solid. MS m/z=290 [M+H]⁺. Calc'd forC₁₂H₁₄F₃N₃O₂: 289.

Step 3:(S)-N,N-dimethyl-1-(2-nitro-4-(trifluoromethyl)phenyl)piperidin-3-amine

To a yellow solution of(S)-1-(2-nitro-4-(trifluoromethyl)phenyl)piperidin-3-aminedihydrochloride (13.39 g, 37 mmol) in 123 mL MeOH under nitrogen at 0°C. was added formaldehyde (37% solution) (14 ml, 185 mmol), Acetic acid(11 ml, 185 mmol), and sodium cyanoborohydride (4.6 g, 74 mmol) inportions over 5 min. The cloudy mixture was warmed to ambienttemperature. After 10 min, the reaction became quite hot and was cooledwith an ice bath. After 1.5 h, the reaction was complete by LCMS. Thesolvent was removed in vacuo, and the flask cooled to 0° C. Water wasadded, and the mixture was basified with 1N NaOH, and 6N NaOH. Themixture was extracted with 1×200 mL EtOAc, 1×100 mL EtOAc, and thecombined organics were dried over anhydrous Na₂SO₄ and concentrated invacuo to give(S)-N,N-dimethyl-1-(2-nitro-4-(trifluoromethyl)phenyl)piperidin-3-amineas an orange oil. MS m/z=318 [M+H]⁺. Calc'd for C₁₄H₁₈F₃N₃O₂: 317.

Step 4:(S)-1-(2-amino-4-(trifluoromethyl)phenyl)-N,N-dimethylpiperidin-3-amine

A 500 mL parr pressure bottle was charged with palladium, 10 wt. % onactivated carbon, 50% water wet (9.1 g, 8.6 mmol) under nitrogen.(S)-N,N-dimethyl-1-(2-nitro-4-(trifluoromethyl)phenyl)piperidin-3-amine(13.6 g, 43 mmol) was added as a solution in methanol via syringe,rinsing in with multiple methanol washes until the final volume wasapproximately 100 mL. The vessel was placed in a parr shaker, andtreated with 2 atm H₂ and shaken overnight. The reaction was flushedwith nitrogen, and filtered through a pad of celite rinsing with 1.3 Lof methanol and concentrated in vacuo. The oil was taken up in CH₂Cl₂,dried over Na₂SO₄, filtered, and concentrated in vacuo to give(S)-1-(2-amino-4-(trifluoromethyl)phenyl)-N,N-dimethylpiperidin-3-amineas a red oil. MS m/z=288 [M+H]⁺. Calc'd for C₁₄H₂₀F₃N₃: 287.

Example 167 was also made by a different method as described in Example125 herein.

Example 168

(R)-1-(2-amino-4-(trifluoromethyl)phenyl)-N,N-dimethylpiperidin-3-amine

The title compound was synthesized using a procedure similar to thatdescribed in Example 167. MS m/z=288 [M+H]⁺. Calc'd for C₁₄H₂₀F₃N₃: 287.

Example 169

(R)-2-(3-((dimethylamino)methyl)pyrrolidin-1-yl)-5-(trifluoromethyl)benzenamine

The title compound was synthesized using a procedure similar to thatdescribed in Example 167. MS m/z=288 [M+H]⁺. Calc'd for C₁₄H₂₀F₃N₃: 287.

Example 170

(4-(2-amino-4-(trifluoromethyl)phenyl)piperazin-2-one

The title compound was synthesized using a procedure similar to thatdescribed in pending U.S. Patent Application No. 60/569,193. MS m/z=260[M+H]⁺. Calc'd for C₁₁H₁₂F₃N₃O: 259.

Example 171

Synthesis of 4-(2-nitro-4-(trifluoromethyl)phenyl)thiomorpholine

To a solution of 1-fluoro-2-nitro-4-(trifluoromethyl)benzene (7.00 g,33.48 mmol) in THF (250 ml) at room temperature was added thiomorpholine(3.45 g, 33.48 mmol) and sodium bicarbonate (3.66 g, 43.52 mmol). Thevessel was purged with nitrogen and stirred at room temperature for 48hours. After removal of solvent under reduced pressure, the mixture wastaken up in ethyl acetate and filtered. The organics were washed withwater, then brine and dried with magnesium sulfate. Filtration andconcentration provided the title compound as a bright orange solid. MSm/z: 293.1 (M+H⁺); calc MW=292.28.

Example 172

Synthesis of the sulfoxide of4-(2-nitro-4-(trifluoromethyl)phenyl)thiomorpholine

To a solution of 4-(2-nitro-4-(trifluoromethyl)phenyl)thiomorpholine(2.0 g, 6.84 mmol) in methanol (60 ml) and water (15 ml) was added NaIO₄(1.61 g, 7.53 mmol). The mixture was allowed to stir at room temperaturefor 12 hours, at which time it was filtered to remove white solidprecipitates. Concentration afforded the title compound as an orangesolid. MS m/z: 309 (M+H⁺); calc'd MW=308.28.

Example 173

Synthesis of the sulfone of4-(2-nitro-4-(trifluoromethyl)phenyl)thiomorpholine

To a solution of the sulfoxide of4-(2-nitro-4-(trifluoromethyl)phenyl)thiomorpholine (170 mg, 0.55 mmol)in methanol (50 ml) was added KMNO₄ (96 mg, 0.61 mmol). The reaction wasstirred at room temperature for 15 minutes and then quenched by theaddition of aqueous saturated sodium bisulfate (20 ml). The reaction wasfiltered and concentrated to provide the sulfone product. MS m/z: 325(M+H⁺); calc'd MW=324.28.

The nitro groups of Examples 173-175 were reduced to the correspondingamine by conventional methods, such as be hydrogenation in the presenceof a palladium catalyst. The reduction product of Example 173 was foundto have a MS (m/z)=263.1 (M+H⁺); calc'd MW=262.30, and the reductionproduct of Example 175 was found to have a MS (m/z)=295.1 (M+H⁺); Calc'dMW=294.30.

Example 176

Synthesis of 3-amino-4-methoxy-N-(pyridine-3-yl)benzamide

Step 1: 4-methoxy-3-nitrobenzoic acid (10.0 g, 0.051 mol), and thionylchloride (25 g, 0.212 mol), were refluxed together for 24 hours. Thereaction mixture was cooled to room temperature and concentrated. Theoff-white solid was carried onto the next step.Step 2: 4-methoxy-3-nitrobenzoyl chloride (1.08 g, 0.005 mol),2-aminopyridine (0.94 g, 0.01 mol) and DIPEA (1.8 mL, 0.01 mol) wereallowed to stir in dichloromethane (10 mL) for 48 hours to form4-methoxy-3-nitro-N-(pyridin-2-yl)benzamide. Intermediate was purifiedvia silica column chromatography using 0 to 100% ethyl acetate inhexane.Step 3: Into a 100 mL round bottom flask was placed4-methoxy-3-nitro-N-(pyridin-2-yl)benzamide (0.735 g, 2.69 mmol), 10%Palladium on carbon (250 mg), ethanol (50 mL), and acetic acid (10 mL)under inert atmosphere. Atmosphere then exchanged with hydrogen (viaballoon) and allowed to stir 24 hours at room temperature. Reactionmixture was filtered through celite, concentrated under reducedpressure, then purified via silica column chromatography using 0 to 100%ethyl acetate in hexane. MS m/z=244 [M+H]⁺. Calc'd for C₁₃H₁₃N₃O₂:243.3.

Various different B rings (R² groups), which are contemplated herein,may be commercially purchased or made by various methods, as representedby Examples 177-182a.

Example 177

Synthesis of3-iodo-N-(3-(trifluoromethyl)phenyl)-1H-indole-1-carboxamide

To a solution of 3-iodoindole (583 mg, 2.4 mmol) (Witulski, B.;Buschmann, N.; Bergstrasser, U. Tetrahedron 2000, 56, 8473-8480.) in DMF(10 mL) at 0° C. was added NaH (125 mg, 3.1 mmol, 60% dispersion inmineral oil). The reaction mixture was allowed to warm to roomtemperature and stir for 0.5 h. Then1-isocyanato-3-(trifluoromethyl)benzene (0.38 mL, 2.64 mmol) was addedand allowed to stir for an additional 0.5 h. Sat. aq. NH₄Cl (20 mL) wasadded and the mixture was poured onto water (50 mL). The aqueous layerwas extracted with Et₂O (3×25 mL). The combined organics were washedwith brine (10 mL), dried over anhydrous sodium sulfate, filtered andconcentrated under reduced pressure. The crude concentrate was purifiedvia automated flash chromatography (silica gel, 0 to 50% EtOAc inhexanes, gradient elution) to afford3-iodo-N-(3-(trifluoromethyl)phenyl)-1H-indole-1-carboxamide.

Example 178

5-Bromothiophene-3-carboxylic acid was prepared by a method similar tothat described in Campaigne, E. E.; Bourgeois, R. C. J. Am. Chem. Soc.1954, 76, 2445-7. MS (m/z)=206 (M−H⁺)

Example 179

Synthesis of 5-bromo-2,3,4-trimethoxybenzoic acid

To a solution of 2,3,4-trimethoxybenzoic acid (4.7 g, 22 mmol) and NaOAc(5.5 g, 40 mmol) in 35 ml AcOH was added a solution of bromine (1.5 ml,29 mmol) in 35 ml AcOH. The reaction became red in color, which quicklyfaded. The mixture was heated to 80° C. for 1 h, at which point it wascooled to ambient temperature. The material was partitioned betweendichloromethane and water. The organic layer was removed and the aqueouslayer was extracted once with dichloromethane. The combined organiclayers were dried with Na₂SO₄, filtered, and concentrated to give an oilwhich solidified on standing. The material was dissolved in diethylether and hexanes. Concentration to ½ the volume resulted inprecipitation of a white solid. Filtration provided the title compoundas a white solid. MS m/z: 293 (M+H⁺); calc'd for C₁₀H₁₁BrO₅: 291.1

Example 180

Synthesis of 5-iodo-2-methoxybenzoic acid Step 1. Synthesis of methyl5-iodo-2-methoxy benzoate

To a solution of 5-iodosalicylic acid (10.0 g, 38 mmol) in 189 mlacetone was added potassium carbonate (23 g, 169 mmol). The mixture wascooled to 0° C. and dimethyl sulfate (7.7 ml, 80 mmol) was added. Themixture was heated to reflux overnight and was cooled to ambienttemperature and concentrated under reduced pressure. The residue waspartitioned between EtOAc and water, and the aqueous layer was extractedthree times with EtOAc. The combined organic layers were dried withNa₂SO₄, filtered, and concentrated to give a white solid. This materialwas heated with hexanes and allowed to stand for 60 h, resulting in theformation of crystals. Filtration provided the title compound as whiteneedles. MS (ES⁺): 292.9 (M+H)⁺. Calc'd for C₉H₉IO₃: 292.07.

Step 2. Synthesis of 5-iodo-2-methoxybenzoic acid

A mixture of methyl 5-iodo-2-methoxy benzoate (6.0 g, 21 mmol) and 23 mleach MeOH and 1N NaOH was heated with a water-cooled reflux condensor to90° C. for 2 h. The reaction was cooled to ambient temperature, 100 mLwater was added, and the solution adjusted to pH 1 with 6N HCl. A thickwhite precipitate formed which was collected by filtration to give thetitle compound as a white solid. MS (m/z): 278.9 (M+H)⁺. Calc'd forC₈H₇IO₃: 278.04.

Example 181

Synthesis of 5-chloro-1-methyl-2-oxo-1,2-dihydropyridine-3-carboxylicacid Step 1. Synthesis of methyl5-chloro-1-methyl-2-oxo-1,2-dihydropyridine-3-carboxylate

To a suspension of 5-chloro-2-hydroxynicotinic acid (2.0 g, 12 mmol) andcesium carbonate (8.2 g, 26 mmol) in 50 mL DMF was added MeI (1.6 ml, 26mmol). The reaction was allowed to stir for approximately 12 h. Thecloudy yellow mixture was added to EtOAc/water. The organic layer wasremoved and the aqueous layer was extracted three times with EtOAc. Thecombined organic layers were washed once with water and brine, driedwith Na₂SO₄, filtered, and concentrated to give an orange-yellow solid.The material was partitioned between 1N HCl and EtOAc. The organic layerwas washed twice with 1N HCl, dried with Na₂SO₄, filtered, andconcentrated to give the desired product as an orange solid. MS (m/z):202.0 (M+H)⁺. Calc'd for C₈H₈ClNO₃: 201.61.

Step 2. Synthesis of5-chloro-1-methyl-2-oxo-1,2-dihydropyridine-3-carboxylic acid

A mixture ofmethyl-5-chloro-1-methyl-2-oxo-1,2-dihydropyridine-3-carboxylate (0.36g, 1.8 mmol) and 2.0 mL each MeOH and 1N NaOH was heated in a sealedvial to 80° C. for 1 h. The reaction was cooled to ambient temperature,and the methanol was removed by a stream of nitrogen. Water (2 ml) wasadded and the solution was adjusted to pH 1 with 6N HCl. A thick whiteprecipitate formed which was partitioned between water anddichloromethane. The organic layer was removed and the aqueous layer wasextracted twice with dichloromethane. The combined organic layers weredried with Na₂SO₄, filtered, and concentrated to give an orange-yellowsolid. The material was partitioned between 1N HCl and EtOAc. Theorganic layer was washed twice with 1N HCl, dried with Na₂SO₄, filtered,and concentrated to give the desired product as a light orange solid. MS(m/z): 188.0 (M+H)⁺. Calc'd for C₇H₆ClNO₃: 187.58.

Example 182

5-bromo-2-fluoro-4-methylbenzoic acid was prepared by a method describedin PCT Patent Publication WO 2003/032972.

Example 182a

The title compound was prepared according to a literature procedurepublished in J. Med. Chem. 2001, 44, 1815.

Various different A-B linked ring intermediates (substituted R² groups),which are contemplated herein, may be made by various methods, such aswith A-B amide linked rings, as represented by Examples 183-191.

Example 183

Synthesis of3-bromo-4-fluoro-N-(2-fluoro-3-(trifluoromethyl)phenyl)benzamide

Step 1: 3-Bromo-4-fluorobenzoyl chloride

Oxalyl chloride (1.739 g, 1.20 ml, 13.7 mmol) was added dropwise to asolution of 3-bromo-4-fluorobenzoic acid (0.600 mg, 2.74 mmol) anddichloromethane (9 ml). N,N-Dimethylformamide (1 drop) was added and thecolorless solution stirred at rt for 1 h. The solution was concentratedto afford 3-bromo-4-fluorobenzoyl chloride an off-white solid which wasused directed without purification.

Step 2: 3-Bromo-4-fluoro-N-(2-fluoro-3-(trifluoromethyl)phenyl)benzamide

2-Fluoro-3-(trifluromethyl)aniline (0.515 g, 0.37 mL, 2.88 mmol) wasadded to a solution of 3-bromo-4-fluorobenzoyl chloride (0.650 g, 2.74mmol) in dichloromethane (5 ml), and the mixture stirred at roomtemperature for 30 min. Triethylamine (0.360 g, 0.50 ml, 3.56 mmol) wasadded and the solution stirred at room temperature for 1 h. The reactionmixture was partitioned between dichloromethane and saturated aqueoussodium bicarbonate solution. The aqueous phase was separated andextracted with dichloromethane. The combined organic phases were washedwith water, brine, dried over anhydrous sodium sulfate, filtered, andconcentrated to afford a light yellow solid. Trituration withdichloromethane and filtering afforded3-bromo-4-fluoro-N-(2-fluoro-3-(trifluoromethyl)phenyl)benzamide as awhite solid. MS (M−H⁺) 377.9; Calculated for C₁₄H₇BrF₅NO: 379.

Example 184

Synthesis of 3-Bromo-4-fluoro-N-(3-(trifluoromethyl)phenyl)benzamide

3-Bromo-4-fluoro-N-(3-(trifluoromethyl)phenyl)benzamide was synthesizedfrom 3-trifluoromethylaniline and 3-bromo-4-fluorobenzoyl chlorideaccording to the procedure described in Example 183, affording the titlecompound as a white solid. MS (M−H⁺) 360.0; Calculated for C₁₄H₈BrF₄NO:361.

Example 185

Synthesis of 3-Bromo-N-(5-tert-butyl-2-methoxyphenyl)-4-fluorobenzamide

3-Bromo-N-(5-tert-butyl-2-methoxyphenyl)-4-fluorobenzamide wassynthesized from 5-tert-butyl-o-anisidine and 3-bromo-4-fluorobenzoylchloride according to the procedure described in Example 183, affordingthe title compound as an off-white solid. MS (M+H⁺) 380.0; Calculatedfor C₁₈H₁₉BrFNO₂: 379.

Example 186

Synthesis of 3-Bromo-N-(5-tert-butyl-2-methoxyphenyl)-4-chlorobenzamideStep 1: 3-Bromo-4-chlorobenzoyl chloride

3-Bromo-4-chlorobenzoyl chloride was prepared from3-bromo-4-chlorobenzoic acid according to the procedure described inExample 183 for the synthesis of 3-bromo-4-fluorobenzoyl chloride.

Step 2: 3-Bromo-N-(5-tert-butyl-2-methoxyphenyl)-4-chlorobenzamide

3-Bromo-N-(5-tert-butyl-2-methoxyphenyl)-4-chlorobenzamide wassynthesized from 5-tert-butyl-o-anisidine and 3-bromo-4-chlorobenzoylchloride according to the procedure described in Example 183, step 2.3-Bromo-N-(5-tert-butyl-2-methoxyphenyl)-4-chlorobenzamide was obtainedas an off-white solid. MS (M−H⁺) 394.0; Calculated for C₁₈H₁₉BrClNO₂:395.

Example 187

Synthesis of3-Bromo-4-chloro-N-(2-fluoro-3-(trifluoromethyl)phenyl)benzamide

3-Bromo-4-chloro-N-(2-fluoro-3-(trifluoromethyl)phenyl)benzamide wassynthesized from 2-fluoro-3-(trifluromethyl)aniline and3-bromo-4-chlorobenzoyl chloride according to the procedure described inExample 183.3-Bromo-4-chloro-N-(2-fluoro-3-(trifluoromethyl)phenyl)benzamide wasobtained as a red-orange solid. MS (M−H⁺) 393.9; Calc'd forC₁₄H₇BrClF₄NO: 395.

Example 188

Synthesis of4-Chloro-3-iodo-N-(2-methyl-3-(trifluoromethyl)phenyl)benzamide Step 1:4-Chloro-3-iodobenzoylchloride

4-Chloro-3-iodobenzoylchloride was prepared from 4-chloro-3-iodobenzoicacid according to the procedure described in Example 183 for thesynthesis of 3-bromo-4-fluorobenzoyl chloride.

Step 2: 4-Chloro-3-iodo-N-(2-methyl-3-(trifluoromethyl)phenyl)benzamide

4-Chloro-3-iodo-N-(2-methyl-3-(trifluoromethyl)phenyl)benzamide wassynthesized from 2-methyl-3-(trifluromethyl)aniline and4-chloro-3-iodobenzoyl chloride according to the procedure dscribed inExample 183.4-Chloro-3-iodo-N-(2-methyl-3-(trifluoromethyl)phenyl)benzamide wasobtained as a white solid. MS (M−H⁺) 437.8; Calculated forC₁₅H₁₀ClF₃INO: 439.

Example 189

Synthesis of 4-Chloro-3-iodo-N-(3-(trifluoromethoxy)phenyl)benzamide

4-Chloro-3-iodo-N-(3-(trifluoromethoxy)phenyl)benzamide was synthesizedfrom 3-(trifluoromethoxy)aniline and 4-chloro-3-iodobenzoylchlorideaccording to the procedure described in Example 183, affording the titlecompound as a white solid. MS (M−H⁺) 439.8; Calculated forC₁₄H₈ClF₃INO₂: 441.

The following A-B amide linked ring intermediates, Examples 190-270,were made by methods similar to that described in Example 183.

Example No. Structure 190

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Various different alkyne-substituted heteroaryl C ring (pyridines,pyrimidines, quinolines, quinazolines, imidazolo-pyridines, and thelike), which are contemplated herein, may be made by various methods, asrepresented by Examples 271-275.

Example 271

Synthesis of 2-amino-5-ethynylpyrimidine

Into a 1 L round bottom flask was placed the 2-amino-5-iodopyrimidine(8.0 g, 36.2 mmol), acetonitrile (300 mL), triethylamine (30 mL), TMSacetylene (7.68 g, 78.2 mmol), palladium dichloro-bis-triphenylphosphine(1.26 g, 1.8 mmol), and copper(I) iodide (0.342 g, 1.8 mmol). The vesselwas filled with argon gas and allowed to stir at room temperature for 3hours. The solvent was evaporated and the crude was taken up in methanol(400 mL). Then excess potassium carbonate (10 eq) was added, and themixture was stirred at room temperature for 1.5 hours. Activatedcharcoal was added and the mixture was filtered through celite. Thefiltrate was concentrated under reduced pressure to afford a tan solid,which was added to a solution of 10% methanol in water (200 mL). Theresulting precipitate was isolated by filtration, dried in a vacuum ovento constant mass and afforded the title compound as a tan solid. MSm/z=120 [M+H]⁺. Calc'd for C₆H₅N₃: 119.

Example 272

Synthesis of 5-ethynyl-4-methylpyrimidin-2-amine

The title compound was prepared from 5-iodo-4-methylpyrimidin-2-amine(prepared according to the method described in Sakamoto, T.; Kondo, Y.;Yamanaka, H. Synthesis, 1984, 3, 252-4) in a manner similar to thatdescribed in Example 271 above. MS (m/z): 236 (M+H⁺)

Example 273

5-ethynyl-N-methylpyrimidin-2-amine Step 1:5-bromo-N-methylpyrimidin-2-amine

A mixture of 2-chloro-5-bromopyrimidine (2.5 g, 13 mmol), methylaminehydrochloride (7.9 g, 116 mmol), and diisopropylethylamine (18 mL, 103mmol) in 43 mL acetonitrile was heated in a sealed vessel for 16 h. Thereaction was partitioned between EtOAc and water. The organic layer waswashed once with brine, dried over anhydrous sodium sulfate, filtered,and concentrated to give 5-bromo-N-methylpyrimidin-2-amine. MS m/z=188[M+H]⁺. Calc'd for C₅H₆BrN₃: 187.

Step 2: N-methyl-5-(2-(trimethylsilyl)ethynyl)pyrimidin-2-amine

A 100 mL round bottom flask was charged withpalladium(bisbenzonitrile)dichloride (0.23 g, 0.61 mmol),trit-butylphosphonium tetrafluoroborate (0.35 g, 1.2 mmol) and copper(I) iodide (0.11 g, 0.61 mmol) under argon. 20 mL dioxane was added,followed by diisopropylethylamine (2.6 mL, 18 mmol),5-bromo-N-methylpyrimidin-2-amine (2.3 g, 12 mmol), and trimethylsilylacetylene (3.4 mL, 24 mmol). The reaction was allowed to stir overnight.The cloudy brown mixture was diluted with EtOAc and filtered through apad of silica gel and concentrated in vacuo to give a brown solid. Thiswas further purified by silica gel chromatography, eluting with 0-50%EtOAc/dichloromethane to giveN-methyl-5-(2-(trimethylsilyl)ethynyl)pyrimidin-2-amine as a yellowsolid. MS m/z=206 [M+H]⁺. Calc'd for C₁₀H₁₅N₃Si: 205.

Step 3: 5-ethynyl-N-methylpyrimidin-2-amine

To a slurry of N-methyl-5-(2-(trimethylsilyl)ethynyl)pyrimidin-2-amine(2.4 g, 12 mmol) in 60 mL methanol was added potassium carbonate (4.8 g,35 mmol). The cloudy mixture was allowed to stir rapidly for 4 h. Themixture was then concentrated to a small volume and partitioned betweenwater and dichloromethane. The aqueous layer was extracted 5× withdichloromethane and 2× with EtOAc. The combined organic layers weredried over anhydrous sodium sulfate, filtered, and concentrated in vacuoto give N-methyl-5-(2-(trimethylsilyl)ethynyl)pyrimidin-2-amine as abrown solid. MS m/z=134 [M+H]⁺. Calc'd for C₇H₇N₃: 133.

Example 274

5-ethynyl-N-methyl-4-(thiophen-2-yl)pyrimidin-2-amine Step 1:5-bromo-2-chloro-4-(thiophen-2-yl)pyrimidine

A solution of thiophene (3.3 g, 39 mmol) in THF (100 mL) was cooled to−78° C. n-Butyllithium (2.5 M in hexane, 24 mL, 59 mmol) was added andthe mixture stirred at −78° C. for 1 h. 2-Chloro-5-bromopyrimidine (7.5g, 39 mmol) was added and the mixture stirred at −78° C. for 1 h. DDQ(17.7 g, 78 mmol) was added with stirring, followed by the addition ofmethanol (5 mL). The mixture stirred for 1 h and was then warmed to 0°C. and then to RT. The reaction mixture was poured into 0.5 M sodiumascorbate (aq) solution (100 mL), and allowed to stir for 1 h. Themixture was treated with saturated aqueous potassium carbonate solution(50 mL), and extracted with ethyl acetate. The combined organic layerswere dried over anhydrous sodium sulfate, filtered and concentrated. Theresidue was purified via column chromatography on silica gel (elutingwith 100% dichloromethane) to afford5-bromo-2-chloro-4-(thiophen-2-yl)pyrimidine as a yellow solid. MSm/z=276 [M+H]⁺. Calc'd for C₈H₄BrClN₂S: 275.

Step 2: 5-bromo-N-methyl-4-(thiophen-2-yl)pyrimidin-2-amine

A 16 by 100 mm vial was charged with5-bromo-2-chloro-4-(thiophen-2-yl)pyrimidine (1.00 g, 3.6 mmol), THF (4mL), triethylamine (1.5 ml, 11 mmol), and methylamine hydrochloride(0.49 g, 7.3 mmol), and water (0.4 mL). The vial was capped and heatedto 85° C. with stirring for 20 hours. The reaction was cooled to roomtemperature and concentrated. The residue was purified via columnchromatography on silica gel (gradient elution with 0 to 4% methanol indichloromethane) to afford5-bromo-N-methyl-4-(thiophen-2-yl)pyrimidin-2-amine. MS m/z=271 [M+H]⁺.Calc'd for C₉H₈BrN₃S: 270.

Step 3:N-methyl-4-(thiophen-2-yl)-5-(2-(trimethylsilyl)ethynyl)pyrimidin-2-amine

A 75 mL thick wall glass tube with a teflon screw cap was charged with5-bromo-N-methyl-4-(thiophen-2-yl)pyrimidin-2-amine (0.995 g, 3.68mmol), acetonitrile (9 mL), triethylamine (3.00 ml, 3.68 mmol),dichlorobistriphenylphosphine palladium(II) (0.259 g, 0.368 mmol),copper(I) iodide (0.0351 g, 0.184 mmol), and ethynyltrimethylsilane(0.362 g, 3.68 mmol). The tube was capped and heated to 90° C. for 2hours. The reaction mixture was cooled to room temperature andconcentrated. The residue was purified via column chromatography onsilica gel (gradient elution with 0-100% ethyl acetate-hexane) to affordN-methyl-4-(thiophen-2-yl)-5-(2-(trimethylsilyl)ethynyl)pyrimidin-2-amine.MS m/z=288 [M+H]⁺. Calc'd for C₁₄H₁₇N₃SSi: 287.

Step 4: 5-ethynyl-N-methyl-4-(thiophen-2-yl)pyrimidin-2-amine

A 25 mL round bottom flask was charged withN-methyl-4-(thiophen-2-yl)-5-(2-(trimethylsilyl)ethynyl)pyrimidin-2-amine(0.518 g, 1.80 mmol), methanol (20 mL), and potassium carbonate (0.747g, 5.41 mmol), and the reaction mixture stirred at room temperature for24 hours. The reaction mixture was concentrated and the residue waspurified via column chromatography on silica gel (gradient elution with0-100% ethyl acetate-hexane) to5-ethynyl-N-methyl-4-(thiophen-2-yl)pyrimidin-2-amine. MS m/z=216[M+H]⁺. Calc'd for C₁₁H₉N₃S: 215.

Example 275

2-Bromoquinoxaline was prepared in a manner similar to that described inKato, Y.; Okada, S.; Tomimoto, K.; Mase, Tetrahedron Let. 2001, 42,4849-4851. MS (m/z): 210 (M+H⁺)

Example 276

5-Bromo-N-methylpicolinamide was prepared in a manner similar to thatdescribed in Markevitch, D. Y.; Rapta, M.; Hecker, S. J.; Renau, T. E.Synthetic Commun. 2003, 33, 3285-3289. MS (m/z): 217 (M+H⁺)

Example 277

6-Bromo-3H-imidazo[4,5-b]pyridine was prepared in a manner similar tothat described in Yutilov, Y. M.; Lopatinskaya, K. Y.; Smolyar, N. N.;Korol, I. V. Russian Journal of Organic Chemistry 2003, 39, 280-281. MS(m/z): 199 (M+H⁺)

Example 278

5-bromo-N-(2-morpholinoethyl)pyrimidin-2-amine

A resealable tube was charged with a solution of2-chloro-5-bromopyrimidine (1.00 g, 5.17 mmol),N-(2-aminoethyl)morpholine (0.808 g, 6.20 mmol), diisopropylethylamine(0.801 g, 1.1 mL, 6.20 mmol), and THF (40 mL). The mixture was heated at85° C. for 20 h. The reaction mixture was concentrated and then purifiedvia column chromatography on silica gel (gradient elution with 0-100%(90:10:1, dichloromethane/methanol/ammonium hydroxide)-dichloromethane)to afford 5-bromo-N-(2-morpholinoethyl)pyrimidin-2-amine as a lightyellow solid. MS m/z=288 [M+H]⁺. Calc'd for C₁₀H₁₅BrN₄O: 287.

Example 278a

5-bromo-4-(2-ethoxyphenoxy)-N-(4-(4-methylpiperazin-1-yl)phenyl)pyrimidin-2-amineStep 1. 5-bromo-2-chloro-4-(2-ethoxyphenoxy)pyrimidine

To a suspension of NaH (0.42 g 60% in mineral oil, 10.5 mmol) in DMF(8.0 mL) was slowly added 2-ethoxylphenol (1.34 g, 9.7 mmol) in MeCN(4.0 mL) at 0° C. under N₂. After the addition, the reaction mixture wasallowed to warm up to room temperature for 0.5 hour.5-bromo-2,4-dichloropyrimidine (2.0 g, 8.8 mmol) in MeCN (16.0 mL) wasslowly added and then the resulting reaction mixture was stirred at roomtemperature for 24 hour. EtOAc (120 mL) was added and washed with NaOH(30 mL, 0.5N) and brine (25×2 mL). The organic layer was dried withMgSO₄, and concentrated under reduced pressure. The residue was purifiedby silica gel chromatography (10% to 30% EtOAc in Hexanes, gradientelution) to provide the 5-bromo-2-chloro-4-(2-ethoxyphenoxy)pyrimidine.MS m/z=330 [M+1]⁺. Calc'd for: C₁₂H₁₀BrClN₂O₂: 329

Step 2.5-bromo-4-(2-ethoxyphenoxy)-N-(4-(4-methylpiperazin-1-yl)phenyl)pyrimidin-2-amine

To a solution of 5-bromo-2-chloro-4-(2-ethoxy)pyrimidine (0.8 g, 2.4mmol) and 4-(2-(pyrrolidin-1-yl)ethoxy)benzenamine (0.51 g, 2.7 mmol) in1,4-dioxane (5.0 mL) was added trifluoroacetic acid (0.1 mL). Theresulting reaction mixture was stirred at 90° C. overnight. The reactionmixture was allowed to cool to room temperature, diluted with CH₂Cl₂(200 mL) and washed with sat. aq. NaHCO₃ (20×2 mL) and brine (20×3 mL).The organic layer was dried with MgSO₄, and concentrated under reducedpressure. The residue was purified by silica gel chromatography (10% to50% EtOAc in Hexanes, gradient elution) to get the5-bromo-4-(2-ethoxyphenoxy)-N-(4-(4-methylpiperazin-1-yl)phenyl)pyrimidin-2-amine.MS m/z=485 [M+1]⁺. Calc'd for: C₂₃H₂₆BrN₅O₂: 484

Example 278b

The compound above,5-iodo-4-(2-methoxyphenoxy)-N-(4-(4-methylpiperazin-1-yl)phenyl)pyrimidin-2-amine,was prepared by a method similar to that described in Example 278a. MSm/z=517 [M+H]⁺; Calc'd for: C₂₂H₂₄IN₅O₂; 517.36

Example 278c

5-bromo-N-(4-(4-methylpiperazin-1-yl)phenyl)pyrimidin-2-amine

A resealable tube was charged with 2-chloro-5-bromopyrimidine (1.00 g,5.21 mmol), 4-(N-methylpiperazine)aniline (1.20 g, 6.25 mmol),trifluoroacetic acid (1.78 g, 1.20 mL, 15.6 mmol), and isopropanol (50mL). The tube was sealed and the mixture stirred at 100° C. for 20 h.The reaction mixture was concentrated and the residue was purified viacolumn chromatography on silica gel (gradient elution with 0-100%(90:10:1, dichloromethane/methanol/ammonium hydroxide)-dichloromethane)to afford 5-bromo-N-(4-(4-methylpiperazin-1-yl)phenyl)pyrimidin-2-amine.MS m/z=348, 350 [M+H]⁺. Calc'd for C₁₅H₁₈BrN₅: 348.

General Synthesis of Acid Chlorides

While persons of ordinary skill in the art readily appreciate how tomake an acid chloride, the following Examples 279 and 280 representmethods utilized in making representative compounds of Formulas I-III.

Example 279

3-iodo-4-methylbenzoyl acid chloride

Into a 100 mL round bottom flask is placed 3-iodo-4-methyl benzoic acid(10 g, 38.175 mmol) and thionyl chloride (25 mL, 344 mmol). The reactionwas allowed to stir at reflux for 2 hours. The reaction was cooled toroom temperature and concentrated under reduced pressure. Theconcentrate was placed under high vacuum for about 24 hr and affordedthe title acid chloride as a light yellow solid.

Example 280

3,5-ditert-butyl benzoyl chloride

Oxalyl chloride (0.542 g, 0.37 ml, 4.27 mmol) was added dropwise to asolution of 3,5-di-tert-butylbenzoic acid (0.200 g, 0.853 mmol) anddichloromethane (4 ml). N,N-Dimethylformamide (1 drop) was added and thecolorless solution stirred at RT for 3 h. The solution was concentratedto afford 3,5-di-tert-butylbenzoyl chloride as a yellow oil.

The following acid chlorides were prepared according to the methodsdescribed in Example 280 above. 1-methyl-1H-indole-2-carbonyl chloride,2-chloro-3-(trifluoromethyl)benzoyl chloride,4-chloro-3-(trifluoromethyl)benzoyl chloride, 2-chloro-3-methylbenzoylchloride, and 2-chloro-3-fluorobenzoyl chloride.

The following Examples 281-351, made using many of the building blocksdescribed above, should assist in understanding the present inventionand should not be construed as limiting the scope of the invention.

Ex. Compound MS: No. Structure Name MW M + H Method 281

5-((2-amino-5- pyrimidinyl) ethynyl)-N-(2- (methyl((3R)-1- methyl-3-pyrrolidinyl) amino)-5- (trifluoromethyl) phenyl)-2- (methyloxy)benzamide 524.544 525 A1 282

N-(4-((2-amino-5- pyrimidinyl) ethynyl)phenyl)- 3- (trifluoromethyl)benzamide 382.344 383 B1 283

N-(4-((2-amino-5- pyrimidinyl) ethynyl)phenyl)- 1H-benzimidazol- 2-amine326.362 327 C2 284

5-((2-amino-5- pyrimidinyl) ethynyl)-N- (2-((3S)-3- dimethyl- amino)-1-piperidinyl)-5- (trifluoromethyl) phenyl)-2- fluorobenzamide 526.535 527A1 285

N-(4-((2-amino-5- pyrimidinyl) ethynyl)-1-naph- thalenyl)-1H-ben-zimidazol-2- amine 376.421 377 C2 286

5-((2-amino-5- pyrimidinyl) ethynyl)-N-(2-(4- (dimethylamino)-1-piperidinyl)-5- (trifluoromethyl) phenyl)-2- fluorobenzamide 526.535527 A1 287

5-((2-amino-5- pyrimidinyl) ethynyl)-2-fluoro- N-(2-(1-(trifluoro-methyl)phenyl) benzamide 483.467 484 A1 288

5-((2-amino-5- pyrimidinyl) ethynyl)-2-fluoro- N-(2-(2-oxo-1-pyrrolidinyl)-5- (trifluoromethyl) phenyl)benzamide 483.423 484 A1 289

2-fluoro-5-((2- (methylamino)-5- pyrimidinyl) ethynyl)-N-(2-(methyl((3R)-1- methyl-3- pyrrolidinyl) amino)-5- (trifluoromethyl)phenyl)benzamide 526.535 527 A1 290

5-((2-amino-5- pyrimidinyl) ethynyl)-2-fluoro- N-(2-(4-methyl-1-piperazinyl)-5- (trifluoromethyl) phenyl)benzamide 498.482 499 A1 291

5-((2-amino-5- pyrimidinyl) ethynyl)-2-fluoro- N-(2-(2-oxo-1,3-oxazolidin-3-yl)- 5-(trifluoro- methyl)phenyl) benzamide 485.396 486 A1292

5-((2-amino-5- pyrimidinyl) ethynyl)-2-fluoro- N-(2-(3-methyl-2-oxo-1-imidazol- idinyl)-5- (trifluoromethyl) phenyl)benzamide 498.438499 A1 293

5((2-amino-5- pyrimidinyl) ethynyl)-N-(2- ((3R)-3- (dimethylamino)-1-piperidinyl)-5- (trifluoromethyl) phenyl)-2- fluorobenzamide 526.535527 A1 294

5-((2-amino-5- pyrimidinyl) ethynyl)-2-fluoro- N-(2-(3-oxo-1-piperazinyl)-5- (trifluoromethyl) phenyl)benzamide 498.438 499 A1 295

5-((2-amino-5- pyrimidinyl) ethynyl)-N-(2- ((3R)-3- ((dimethylamino)methyl)-1- pyrrolidinyl)-5- (trifluoromethyl) phenyl)-2- fluorobenzamide526.535 527 A1 296

3-((2-amino-5- pyrimidinyl) ethynyl)-N-(4-((2- (dimethylamino)ethyl)oxy) phenyl)-4- methylbenzamide 415.495 416 A1 297

3-((2-amino-5- pyrimidinyl) ethynyl)-4- methyl-N-(4- (trifluoromethyl)-2-pyridinyl) benzamide 397.359 398 A1 298

3-((2-amino-5- pyrimidinyl) ethynyl)-N-(2- fluoro-5- (trifluoromethyl)phenyl)-4- methylbenzamide 414.361 415 A1 299

3-((2-amino-5- pyrimidinyl) ethynyl)- 4-methyl-N-(2- (methyloxy)-5-(trifluoromethyl) phenyl)benzamide 426.396 427 A1 300

3-((2-amino-5- pyrimidinyl) ethynyl)- N-(4-ethyl-2- pyridinyl)-4-methylbenzamide 357.415 358 A1 301

4-methyl-3-((2-((2- (4-morpholinyl) ethyl)amino)-5- pyrimidinyl)ethynyl)-N-(3- (trifluoromethyl) phenyl)benzamide 509.529 510 D1 302

4-((2-amino-5- pyrimidinyl) ethynyl)- N-(2-fluoro-5- (trifluoromethyl)phenyl)-3- methylbenzamide 414.361 415 A1 303

4-methyl-3-((2- ((4-(4-methyl-1- piperazinyl) phenyl)amino)-5-pyrimidinyl) ethynyl)-N-(3- (trifluoromethyl) phenyl)benzamide 570.616571 D1 304

3-((6-amino-3- pyridinyl) ethynyl)-4- methyl-N-(3- (trifluoromethyl)phenyl)benzamide 395.382 396 D1 305

3-((2-amino-5- pyrimidinyl) ethynyl)-4- methyl-N-(4-(4- (1-methylethyl)-1-piperazinyl) phenyl)benzamide 454.575 455 A1 306

3-((2-amino-5- pyrimidinyl) ethynyl)-N-(4- (1,1-dimethyl-ethyl)-3-((N,N- dimethylglycyl) amino)phenyl)-4- methylbenzamide 484.601485 A1 307

3-((2-amino-5- pyrimidinyl) ethynyl)-N-(5,5- dimethyl-3-oxo-1-cyclohexen- 1-yl)-4- methylbenzamide 374.442 375 A1 308

3-((2-amino-5- pyrimidinyl) ethynyl)-N-(3-(1, 1-dimethylethyl)-1-methyl-1H- pyrazol-5-yl)-4- methylbenzamide 388.473 389 A1 309

3-((2-amino-5- pyrimidinyl) ethynyl)- N-(5-(1,1- dimethylethyl)-2-(methyloxy) phenyl)-4- methylbenzamide 414.506 415 A1 310

3-((2-amino-5- pyrimidinyl) ethynyl)-N-(3- ((dimethylamino) methyl)-5-(trifluoromethyl) phenyl)-4- methylbenzamide 453.466 454 A1 311

4-((2-amino-5- pyrimidinyl) ethynyl)- 3-methyl-N-(3- ((4-methyl-1-piperazinyl) methyl)-5- (trifluoromethyl) phenyl)benzamide 508.545 509A1 312

3-((2-amino-5- pyrimidinyl) ethynyl)- 4-methyl-N-(3-(2- oxo-1-pyrrolidinyl)-5- (trifluoromethyl) phenyl)benzamide 479.46 480 A1 313

N-(3-((2-amino-5- pyrimidinyl) ethynyl)- 2-methylphenyl)- 3-(trifluoromethyl) benzamide 396.371 397 A1 314

3-((2-amino-5- pyrimidinyl) ethynyl)- 4-methyl-N-(3-(1- pyrrolidinyl-methyl)-5- (trifluoromethyl) phenyl)benzamide 479.504 480 A1 315

3-((2-amino-5- pyrimidinyl) ethynyl)- 4-methyl-N-(3-(4- morpholinyl-methyl)-5- (trifluoromethyl) phenyl)benzamide 495.503 496 A1 316

3-((2-amino-4- methyl-5- pyrimidinyl) ethynyl)- 4-methyl-N-(3-((4-methyl-1- piperazinyl) methyl)-5- (trifluoromethyl) phenyl)benzamide522.572 523 A1 317

3-((2-amino-5- pyrimidinyl) ethynyl)- 4-methyl-N-(2-(2- oxo-1-pyrrolidinyl)-5- (trifluoromethyl) phenyl)benzamide 479.46 480 A1 318

3-((2-amino-5- pyrimidinyl) ethynyl)- 4-methyl-N-(2-(2- oxo-1,3-oxa-zolidin-3-yl)-5- (trifluoromethyl) phenyl)benzamide 481.432 482 A1 319

3-((2-amino-5- pyrimidinyl) ethynyl)- N-(4-cyano-2- pyridinyl)-4-methylbenzamide 354.372 355 A1 320

3-((2-amino-5- pyrimidinyl) ethynyl)-(4- methyl-N-(3-(3- (4-morpholinyl)propyl)-5- (trifluoromethyl) phenyl)benzamide 523.556 524 A1 321

4-methyl-3-((2- (methylamino)-5- pyrimidinyl) ethynyl)- N-(3-((4-methyl-1-piperazinyl) methyl)-5- (trifluoromethyl) phenyl)benzamide 522.572 523A1 322

3-((2-amino-5- pyrimidinyl) ethynyl)- 4-methyl-N-(3-(3- (4-methyl-1-piperazinyl) propyl)-5- (trifluoromethyl) phenyl)benzamide 536.599 537A1 323

3-((2-amino-5- pyrimidinyl) ethynyl)- N-(3-(3- (dimethylamino)-1-propyn-1-yl)-5- (trifluoromethyl) phenyl)-4- methylbenzamide 477.488478 A1 324

3-((2-amino-5- pyrimidinyl) ethynyl)-N-(2-(3- (dimethylamino)-1-propyn-1-yl)-5- (trifluoromethyl) phenyl)-4- methylbenzamide 477.488478 A1 325

N-(3-((2-amino-5- pyrimidinyl) ethynyl)- 4-methylphenyl)- 3-(trifluoromethyl) benzamide 396.371 397 A1 326

4-methyl-N-(3- ((4-methyl-1- piperazinyl) methyl)-5- (trifluoromethyl)phenyl)-3-(3- pyridinylethynyl) benzamide 492.542 493 A1 327

4-methyl-3-((2- (methylamino)-5- pyrimidinyl) ethynyl)-N-(3-(1-methyl-4- piperidinyl)-5- (trifluoromethyl) phenyl)benzamide507.557 508 A1 328

4-methyl-N-(2-(2- oxo-1- pyrrolidinyl)-5- (trifluoromethyl)phenyl)-3-(3- pyridinylethynyl) benzamide 463.457 464 A1 329

4-methyl-3-((2- (methylamino)-4- (2-thienyl)-5- pyrimidinyl) ethynyl)-N-(3-((4-methyl- 1-piperazinyl) methyl)-5- (trifluoromethyl)phenyl)benzamide 604.698 605 A1 330

4-methyl-3-((2- ((1-methylethyl) amino)-5- pyrimidinyl) ethynyl)-N-(3-((4-methyl)- 1-piperazinyl) methyl)-5- (trifluoromethyl)phenyl)benzamide 550.626 551 A1 331

4-((2-amino-5- pyrimidinyl) ethynyl)- N-(2-(methyl ((3R)-1-methyl-3-pyrrolidinyl) amino)-5- (trifluoromethyl) phenyl)-1- (methyloxy)-2-naphthalene- carboxamide 574.604 575 A1 332

4-methyl-3-((4- ((2-(methyloxy) phenyl) oxy)-2-((4-(4- methyl-1-piperazinyl) phenyl)amino)-5- pyrimidinyl) ethynyl)-N-(3-(trifluoromethyl) phenyl)benzamide 692.739 693 D1 333

N-(3-methyl-4- ((4-((2- (methyloxy) phenyl)oxy)-2- ((4-(4- methyl-1-piperazinyl) phenyl) amino)-5- pyrimidinyl) ethynyl) phenyl)-N′-(3-(trifluoromethyl) phenyl)urea 707.753 708 D1 334

5-((2-amino-5- pyrimidinyl) ethynyl)- N-(2-(3,3- dimethyl-2-oxo-1-azetidinyl)-5- (trifluoromethyl) phenyl)-2- (methyloxy) benzamide509.486 510 A1 335

5-((2-amino-5- pyrimidinyl) ethynyl)- 2-fluoro-N-(2-(4-thiomorpholinyl)- 5-(trifluoro- methyl)phenyl) benzamide 501.506 502 A1336

5-((2-amino-5- pyrimidinyl) ethynyl)- 2-fluoro-N-(2- (methyl(1-methyl-4-piperidinyl) amino)-5- (trifluoromethyl) phenyl)benzamide 526.535 527A1 337

5-((2-amino-5- pyrimidinyl) ethynyl)- 2-fluoro-N-(2- ((4-methyl-1-piperazinyl) methyl)-5- (trifluoromethyl) phenyl)benzamide 512.509 513A1 338

5-((2-amino-5- pyrimidinyl) ethynyl)- 2-fluoro-N-(2-(4- morpholinyl)-5-(trifluoromethyl) phenyl)benzamide 485.439 486 A1 339

5-((2-amino-5- pyrimidinyl) ethynyl)-N-(2- ((3S)-3- (dimethylamino)-1-pyrrolidinyl)-5- (trifluoromethyl) phenyl)-2- fluorobenzamide 512.509513 A1 340

5-((2-amino-5- pyrimidinyl) ethynyl)- 2-fluoro-N-(2- ((2-(4-morpholinyl) ethyl)oxy)-5- (trifluoromethyl) phenyl)benzamide 529.492530 A1 341

5-((2-amino-5- pyrimidinyl) ethynyl)- 2-fluoro-N-(2- ((1S,4R)-5-methyl-2,5- diazabicyclo [2.2.1]hept-2-yl)- 5-(trifluoro- methyl)phenyl)benzamide 510.493 511 A1 342

5-((2-amino-5- pyrimidinyl) ethynyl)- 2-fluoro-N-(2- ((2-(1-pyrrolidinyl) ethyl)oxy)-5- (trifluoromethyl) phenyl)benzamide 513.493514 A1 343

5-((2-amino-5- pyrimidinyl) ethynyl)-N-(2- (((3S)-1-ethyl-3-pyrrolidinyl) oxy)-5- (trifluoromethyl) phenyl)-2- fluorobenzamide513.495 514 A1

344

5-((2-amino-5- pyrimidinyl) ethynyl)- N-(2-(((3S)-1- ethyl-3-piperidinyl)oxy)- 5-(trifluoro- methyl)phenyl)-2- fluorobenzamide 527.52528 A1

345

N-(2-((3S)-3- (dimethylamino)- 1-piperidinyl)-5- (trifluoromethyl)phenyl)-2-fluoro- 5-((2-(methyl- amino)-5- pyrimidinyl) ethynyl)benzamide 540.562 541 A1 346

5-((2-amino-4- methyl-5- pyrimidinyl) ethynyl)-N-(2- ((3S)-3-(dimethylamino)- 1-piperidinyl)-5- (trifluoromethyl) phenyl)-2-fluorobenzamide 540.562 541 A1 347

N-cyclopropyl-4- methyl-3-((2-((2- (4-morpholinyl) ethyl)amino)-5-pyrimidinyl) ethynyl) benzainide 405.499 406 A1 348

N-(4-((2-((4-(4- methyl-1 piperazinyl) phenyl)amino)-5- pyrimidinyl)ethynyl) phenyl)-1H- benzimidazol-2- amine 500.607 501 C2 349

N-(4-((2-((4-(4- methyl-1 piperazinyl) phenyl)amino)-5- pyrimidinyl)ethynyl)- phenyl)-3- (trifluoromethyl) benzamide 556.589 557 B1 350

4-((2-((4-(4- methyl-1- piperazinyl) phenyl)amino)-5- pyrimidinyl)ethynyl)-N-(3- trifluoromethyl) phenyl)benzamide 556.589 557 A1 351

N-(4-((-amino-5- pyrimidinyl) ethynyl)phenyl)-2- (phenylamino) benzamide405.459 406 B1

Biological Evaluation

The following assays can be employed to determine the degree of activityof a compound as a protein kinase inhibitor. Compounds described hereinhave been tested in one or more of these assays, and have shownactivity. Representative compounds of the invention were tested andfound to exhibit IC₅₀ values of 25 μM or less in any one of thedescribed assays, thereby demonstrating and confirming the utility ofthe compounds of the invention as protein kinase inhibitors and in theprophylaxis and treatment of immune diseases, proliferative disorders,angiogenic diseases, etc.

TIE-2-Homogenous Time Resolved Flourescent (HTRF) Kinase Assay

IC₅₀'s for the inhibition of the Tie-2 kinase enzyme for individualcompounds were measured using an HTRF assay, utilizing the followingprocedure:

In a 96 well plate (available from Costar Co.) was placed 1 uL of eachtest and standard compound per well in 100% DMSO having a 25 uM finalcompound concentration (3-fold, 10 point dilution). To each well wasadded 20 uL of a reaction mix formed from Tie-2 (4.0 uL; of a 10 mmstock solution available from Gibco), 0.05% BSA (0.1 uL; from a 10%stock solution available from Sigma-Aldrich Co.), 0.002 mM of BLC HER-2KKK (Biotinylated Long chain peptide; 0.04 uL; from a 0.002 mM stocksolution), 0.01 mM concentration of ATP (0.02 uL; commercially availablefrom Sigma-Aldrich Co.) and the remaining solution was water (15.84 uL)to make to a total volume of 20 uL/well.

The reaction was initiated in each well by adding 20 uL per well of anenzyme preparation consisting of a 50 mM concentration of Hepes (1.0 uL;from a 1000 mM stock solution commercially available from Gibco Co.),0.05% concentration of BSA (0.1 uL), 4 mM of DTT (0.08 uL; from a 1000mM stock solution available from Sigma-Aldrich Co.), a 2.4×10⁻⁷concentration of Tie-2 (0.02 uL, from a 4 mM concentration stock), withthe remaining volume being water (18.8 uL) to dilute the enzymepreparation to a total volume of 20 uL. The plate was incubated forabout 90 minutes at RT. After incubation, a 160 uL of a filtereddetection mixture, prepared from 0.001 mg/ml of SA-APC (0.0765 uL;available as a 2.09 mg/ml stock solution from Gibco), 0.03125 nMconcentration of Eu-Ab (0.1597 uL; available in a 31.3 nM stock solutionfrom Gibco), with the remaining volume being Detection buffer (159.73uL), was added to each well to stop the reaction therein. The plate wasthen allowed to equilibrate for about 3 hr and read on a Ruby Starfluorescent reader (available from BMG Technologies, Inc.) using a 4parameter fit using activity base to calculate the corresponding IC₅₀'sfor the test and standard compounds in each well. The followingexemplary compounds were found to have IC₅₀'s for the inhibition ofTie-2 as measured by the HTRF assay of less than or equal to 10 uM:Examples 1-44, 46-64, 66-67, 69-77, 79 and 81-92.

TIE-2 Cell-Based Delfia Assay

Day 1—Plate Preparation

Three 175 ml flasks of EAHY926 cells were obtained from the Universityof N. Carolina. All cells were trypsinized (i.e., washed with 20 mL ofPBS followed by 3 mL of trypsin-EDTA obtained from Gibco Co., cat. no.25300-054, for 5 min at RT), then cultured in a growth medium solutioncontaining DMEM (High glucose, Gibco Co., cat. no. 1965-092), 10% FBSserum (Gibco Co., cat. no. 10099-141) and P/S(Penicillin-Streptomycin-Glutamine; Gibco Co., cat. no. 10378-016)culture media. The cells were counted using a Z2® Coulter® counter. Thecells were plated in four 24-well tissue culture plates (Costar Co.,cat. no. 353047) to initially contain 4×10⁵ cells/ml per well, and thenloaded to 500 uL volume having a final cell density of 2×10⁵ cells/well.The cells were incubated for 5 or more hours at 37° C. under 5% CO₂. TheDMEM+10% serum+P/S culture media was removed and the cells washed twicewith 500 uL of PBS (without Ca+ and Mg++; Gibco Co., cat. no. 14190-136)at RT. 500 uL of 0.5% FBS+F12 (F12 nutrient mixture; Gibco Co., cat. no.11765-054) was added to each well and the cells were incubated at 37° C.overnight (about 15 hr).

100 ug of anti-hTie2 antibody (R & D Systems, Inc., Cat. No. AF313) wasdiluted with 10 mL of ice-cold PBS to prepare a 10 ug/mL antibodyconcentration stock. A 96-well microplate (Perkin-Elmer Wallac, cat. no.AAAND-0001) was coated with 100 uL of the anti-Tie2 antibody stock andthe coated plate was stored at 4° C. overnight.

Day 2—Compound Plate Preparation

The media in the microplate was replaced with a preparation of 500 uLDMEM+1% BSA (Bovine Serum Albumin; ICN Biomedicals, Inc., cat. no.160069). 20 uL of a selected Tie2 reference compound was placed in aselected well of the 96-well plate, and diluted 1:4 with 100% DMSO froman initial concentration of about 10 mM to a final concentration ofabout 2.5 mM, then diluted 1:3 with 100% DMSO for a 10 point dilution toa final concentration of about 0.128 uM.

Test compounds (10 uL of a 10 mM concentration) were similarly diluted1:4 with 100% DMSO to obtain a sample concentration of about 2.5 mM,then diluted 1:3 for a 10 point dilution to finally obtain aconcentration of about 0.128 uM for each test compound. 20 uL of 100%DMSO served as positive controls, while and 10 uL of the 2.5 mMconcentration of the reference compound served as the negative control.

A 2 uL aliquot from each well (test compounds, positive and negativecontrols) in the 96-well plate was added to designated wells in the24-well cell culture plate (1:250). The culture plate was incubated for2.5 at 37° C. in an atmosphere of about 5% CO₂.

The Tie-2 ligand was stimulated with the following series ofpreparations: (1) about 0.5 mL of a protease inhibitor cocktail(Sigma-Aldrich Co., cat. no. P8340) was thawed; (2) to prepare thephosphatase inhibitor, a 300 mM NaVO₄ (Sigma-Aldrich Chem. Co., cat. no.S6508-10G) stock solution in PBS was made and stored at RT. Two 1 mLaliquots of the NaVO₄ solution was prepared in separate two vials byadding 100 uL of the NaVO₄ stock solution to 900 uL RT PBS and eachsolution was activated by adding 6 uL of H₂O₂ to each vial. Both NaVO₄solutions were mixed, wrapped in aluminum foil and stored at RT for 15min.

The Delfia plates, containing 200 uL of PBS+0.1% TWEEN20, were washedthree times and blocked by adding 200 uL of a diluted solution of 5% BSA(16 mL of stock 7.5% BSA solution, available from Perkin-Elmer Wallac,Cat. No. CR⁸⁴-100, was diluted with 8 mL of room temperature PBS). Theplates were then stored at room temperature for about one hour.

100 uL of 35% BSA solution was diluted with 3.4 mL of ice cold PBS tomake a 1% BSA/PBS solution. 100 uL of this 1% BSA/PBS solution wasdiluted with 900 uL of ice cold PBS. hAng1 was reconstituted with 250 uLof ice cold PBS+0.1% BSA to make a 100 ug/mL concentration in solution.The solution was separated into 70 uL aliquots and stored at −80° C.

1 mL of the 30 mM solution of NaVO₄/PBS was diluted with 99 mL of icecold PBS to form a 300 uM concentration. The solution was kept cold onice. 210 uL of the activated NaVO₄ and 280 uL of the protease inhibitorpreparation was added to 21 mL of RIPA buffer and kept cold on ice.

Dilute hAng1 and Stimulate Cells:

70 uL of the 100 ug/mL stock solution was added to 700 uL in 1% BSA/DMEM(1:10) to 10 ug/mL concentration, and it was stored on ice. 5 uL of this10 ug/mL hAng1 preparation was added to each well of the 24-well plate.The plate was shaken at 700 rpm at 37° C. for about 2.5 minutes.

After shaking, the wells were incubated for 7.5 min at 37° C. The mediawas removed and 400 uL of ice cold PBS+300 uM NaVO₄ was added. The wellswere kept on ice for at least 5 min and washed 1× with ice cold PBS+300uM NaVO₄. The wells were tapped against a dry paper towel. The cellswere lysed with 150 uL of RIPA, 300 uM of NaVO₄, and 100 uL/1*10⁷ cellsprotease inhibitor cocktail (purchased from Sigma-Aldrich, Cat. No.P8340). The solution was incubated, then shaken on ice for 30 min.

The BSA blocking solution was removed from the 96-well plates, whichwere then tapped dry. 140 uL of cell lysate was added to theantibody-coated plate and the plate was incubated at 4° C. for 2 hours.

Delfia 25× Wash Buffer Concentrate (purchased from Perkin-Elmer Wallac,Cat. No. 1244-114) was diluted with 24 parts DDI water to obtain awashing solution. The lysate was removed and the plate was washed threetimes each with 400 uL of Delfia washing solution. The plate was tapdried with a paper towel.

The Anti-Phosphotyrosine clone 4G10 (purchased from Upstatebiotech Co.,Cat. No. 05-321) was diluted with Delfia Assay Buffer (purchased fromPerkin-Elmer Wallac, cat. no. 1244-1111) to make a solution of about 1ug/mL in concentration. 100 uL of antibody was added to the plate andthe plate was incubated at room temperature for one hour. The plate wasagain washed three times with 400 uL pre-time of the Delfia Washingsolution.

The Eu-N1 labeled anti-mouse antibody (purchased from Perkin-ElmerWallac, cat. no. AD0124) was diluted with Delfia Assay Buffer to make asolution of about 0.1 ug/mL in concentration.

100 uL of antibody was added to the plate and the plate was incubated atroom temperature for one hour. The plate was again washed with DelfiaWash Buffer three times as described above. 100 uL of Delfia EnhancementSolution (purchased from Perkin-Elmer Wallac, Cat. No. 1244-105) wasadded to each well and the plate was incubated at room temperature for 5min in the dark.

The Europium signal was measured with a Victor multilabel counter(Wallac Model 1420) while shaking (shake fast, linear, 0.10 mm for 1 s)using a Europium protocol.

Raw data was analyzed using a fit equation in XLFit. IC₅₀ values werethen determined using Grafit software. A majority of the compounds ofExamples 1-92 were found to have an IC₅₀ of less than 25 μM in the Tie-2cell-based Delfia assay.

The compounds of the invention also were found to have inhibitoryactivity with respect to other kinase enzymes as well. For example, thecompounds were found to be inhibitors of Lck. The exemplary assaysdescribed as follows were used to make such determination.

LCK-Homogenous Time Resolved Flourescent (HTRF) Kinase Assay

The LCK HTRF assay begins with LCK in the presence of ATPphosphorylating the biotinylated peptide Gastrin. The reaction incubatesfor 90 min. To quench the assay detection reagents are added which bothstop the reaction by diluting out the enzyme and chelating the metalsdue to the presence of EDTA. Once the detection reagents are added theassay incubates for 30 min to allow for equilibration of the detectionreagents.

The LCK HTRF assay is comprised of 10 μL of compound in 100% DMSO, 15 μLof ATP and biotinylated Gastrin, and 15 μL of LCK KD GST (225-509) for afinal volume of 40 μL. The final concentration of gastrin is 1.2 μM. Thefinal concentration of ATP is 0.5 μm (Km app=0.6 μM+/−0.1) and the finalconcentration of LCK is 250 μM. Buffer conditions are as follows: 50 mMHEPES pH 7.5, 50 mM NaCl, 20 mM MgCl, 5 mM MnCl, 2 mM DTT, 0.05% BSA.

The assay is quenched and stopped with 160 μL of detection reagent.Detection reagents are as follows: Buffer made of 50 mM Tris, pH 7.5,100 mM NaCl, 3 mM EDTA, 0.05% BSA, 0.1% Tween20. Added to this bufferprior to reading is Steptavidin allophycocyanin (SA-APC) at a final concin the assay of 0.0004 mg/mL, and europilated anti-phosphotyrosine Ab(Eu-anti-PY) at a final conc of 0.025 nM.

The assay plate is read in either a Discovery or a RubyStar. Theeu-anti-PY is excited at 320 nm and emits at 615 nm to excite the SA-APCwhich in turn emits at 655 nm. The ratio of SA-APC at 655 nm (exciteddue to close proximity to the Eu-anti-PY because of phosphorylation ofthe peptide) to free Eu-anti-PY at 615 nm will give substratephosphorylation.

Assays for other kinases are done in a similar way as described above,varying the concentrations of enzyme, peptide substrate, and ATP addedto the reaction, depending on the specific activity of the kinase andmeasured Km's for the substrates.

Human Mixed Lymphocyte Reaction (huMLR):

The purpose of this assay is to test the potency of T cell activationinhibitors in an in vitro model of allogeneic T cell stimulation. Humanperipheral blood lymphocytes (hPBL; 2×10⁵/well) are incubated withmitomycin C-treated B lymphoblastoid cells (JY cell line; 1×10⁵/well) asallogeneic stimulators in the presence or absence of dilutions ofpotential inhibitor compound in 96-well round-bottom tissue cultureplates. These cultures are incubated at 37° C. in 5% CO₂ for 6 daystotal. The proliferative response of the hPBL is measured by³H-thymidine incorporation overnight between days 5 and 6 afterinitiation of culture. Cells are harvested onto glass fiber filters and³H-thymidine incorporation into DNA is analyzed by liquid scintillationcounter.

Jurkat Proliferation/Survival Assay:

The purpose of this assay is to test the generalanti-proliferative/cytotoxic effect of compounds on the Jurkat human Tcell line. Jurkat cells (1×10⁵/well) are plated in 96-well flat-bottomtissue culture plates with or without compound dilutions and culturedfor 72 h at 37° C. in 5% CO₂. Viable cell number is determined duringthe last 4 h of culture by adding 10 μL/well WST-1 dye. WST-1 dyeconversion relies on active mitochondrial electron transport forreduction of the tetrazolium dye. The dye conversion was read by OD at450-600 nm.

Anti-CD3/CD28-Induced T Cell IL-2 Secretion and Proliferation Assay:

The purpose of this assay is to test the potency of T cell receptor(TCR; CD3) and CD28 signaling pathway inhibitors in human T cells. Tcells are purified from human peripheral blood lymphocytes (hPBL) andpre-incubated with or without compound prior to stimulation with acombination of an anti-CD3 and an anti-CD28 antibody in 96-well tissueculture plates (1×10⁵ T cells/well). Cells are cultured for ˜20 h at 37°C. in 5% CO₂, then secreted IL-2 in the supernatants is quantified bycytokine ELISA (Pierce/Endogen). The cells remaining in the wells arethen pulsed with ³H-thymidine overnight to assess the T cellproliferative response. Cells are harvested onto glass fiber filters and³H-thymidine incorporation into DNA is analyzed by liquid scintillationcounter. For comparison purposes, phorbol myristic acid (PMA) andcalcium ionophore can be used in combination to induce IL-2 secretionfrom purified T cells. Potential inhibitor compounds can be tested forinhibition of this response as described above for anti-CD3 and -CD28antibodies.

Assays for other kinases are done in a similar way as described above,varying the concentrations of enzyme, peptide substrate, and ATP addedto the reaction, depending on the specific activity of the kinase andmeasured Km's for the substrates.

Exemplary compounds 1-23, 25-54, 56-64, 66-67, 69-77, 81-83 and 85-92exhibited an average IC₅₀ value of 10 uM or less in the human HTRF assayfor the inhibition of the Lck kinase enzyme.

Indications

Accordingly, compounds of the invention are useful for, but not limitedto, the prevention or treatment of inflammation, cancer and relateddiseases. The compounds of the invention have kinase modulatory activityin general, and kinase inhibitory activity in particular. In oneembodiment of the invention, there is provided a method of modulating aprotein kinase enzyme in a subject, the method comprising administeringto the subject an effective dosage amount of a compound of a compound ofFormulae I and II. In another embodiment, the kinase enzyme is ab1, Akt,bcr-ab1, Blk, Brk, Btk, c-kit, c-Met, c-src, c-fms, CDK1, CDK2, CDK3,CDK4, CDK5, CDK6, CDK7, CDK8, CDK9, CDK10, cRaf1, CSF1R, CSK, EGFR,ErbB2, ErbB3, ErbB4, Erk, Fak, fes, FGFR1, FGFR2, FGFR3, FGFR4, FGFR5,Fgr, flt-1, Fps, Frk, Fyn, Hck, IGF-1R, INS-R, Jak, KDR, Lck, Lyn, MEK,p38, PDGFR, PIK, PKC, PYK2, ros, tie, tie2, TRK, Yes or Zap70.

Various of the compounds of the invention have selective inhibitoryactivity for specific kinase receptor enzymes, including Tie-2, Lck, p38and VEGFR/KDR. Accordingly, the compounds of the invention would beuseful in therapy as antineoplasia agents, anti-inflammatory agents orto minimize deleterious effects of Tie-2, Lck; VEGF and/or p38.

Compounds of the invention would be useful for the treatment ofneoplasia including cancer and metastasis, including, but not limitedto: carcinoma such as cancer of the bladder, breast, colon, kidney,liver, lung (including small cell lung cancer), esophagus, gall-bladder,ovary, pancreas, stomach, cervix, thyroid, prostate, and skin (includingsquamous cell carcinoma); hematopoietic tumors of lymphoid lineage(including leukemia, acute lymphocitic leukemia, acute lymphoblasticleukemia, B-cell lymphoma, T-cell-lymphoma, Hodgkin's lymphoma,non-Hodgkin's lymphoma, hairy cell lymphoma and Burkett's lymphoma);hematopoietic tumors of myeloid lineage (including acute and chronicmyelogenous leukemias, myelodysplastic syndrome and promyelocyticleukemia); tumors of mesenchymal origin (including fibrosarcoma andrhabdomyosarcoma, and other sarcomas, e.g. soft tissue and bone); tumorsof the central and peripheral nervous system (including astrocytoma,neuroblastoma, glioma and schwannomas); and other tumors (includingmelanoma, seminoma, teratocarcinoma, osteosarcoma, xenoderomapigmentosum, keratoctanthoma, thyroid follicular cancer and Kaposi'ssarcoma). The compounds are useful for the treatment of neoplasiaselected from lung cancer, colon cancer and breast cancer.

The compounds would also be useful for treatment of ophthalmologicalconditions such as corneal graft rejection, ocular neovascularization,retinal neovascularization including neovascularization following injuryor infection, diabetic retinopathy, retrolental fibroplasia andneovascular glaucoma; retinal ischemia; vitreous hemorrhage; ulcerativediseases such as gastric ulcer; pathological, but non-malignant,conditions such as hemangiomas, including infantile hemaginomas,angiofibroma of the nasopharynx and avascular necrosis of bone; anddisorders of the female reproductive system such as endometriosis. Thecompounds are also useful for the treatment of edema, and conditions ofvascular hyperpermeability.

Based on the ability to modulate kinases impacting angiogenesis, thecompounds of the invention are also useful in treatment and therapy ofproliferative diseases. Particularly, these compounds can be used forthe treatment of an inflammatory rheumatoid or rheumatic disease,especially of manifestations at the locomotor apparatus, such as variousinflammatory rheumatoid diseases, especially chronic polyarthritisincluding rheumatoid arthritis, juvenile arthritis or psoriasisarthropathy; paraneoplastic syndrome or tumor-induced inflammatorydiseases, turbid effusions, collagenosis, such as systemic Lupuserythematosus, poly-myositis, dermato-myositis, systemic sclerodermia ormixed collagenosis; postinfectious arthritis (where no living pathogenicorganism can be found at or in the affected part of the body),seronegative spondylarthritis, such as spondylitis ankylosans;vasculitis, sarcoidosis, or arthrosis; or further any combinationsthereof. An example of an inflammation related disorder is (a) synovialinflammation, for example, synovitis, including any of the particularforms of synovitis, in particular bursal synovitis and purulentsynovitis, as far as it is not crystal-induced. Such synovialinflammation may for example, be consequential to or associated withdisease, e.g. arthritis, e.g. osteoarthritis, rheumatoid arthritis orarthritis deformans. The present invention is further applicable to thesystemic treatment of inflammation, e.g. inflammatory diseases orconditions, of the joints or locomotor apparatus in the region of thetendon insertions and tendon sheaths. Such inflammation may be, forexample, consequential to or associated with disease or further (in abroader sense of the invention) with surgical intervention, including,in particular conditions such as insertion endopathy, myofascialesyndrome and tendomyosis. The present invention is further applicable tothe treatment of inflammation, e.g. inflammatory disease or condition,of connective tissues including dermatomyositis and myositis.

The compounds of the invention can also be used as active agents againstsuch disease states as arthritis, atherosclerosis, psoriasis,hemangiomas, myocardial angiogenesis, coronary and cerebral collaterals,ischemic limb angiogenesis, wound healing, peptic ulcer Helicobacterrelated diseases, fractures, cat scratch fever, rubeosis, neovascularglaucoma and retinopathies such as those associated with diabeticretinopathy or macular degeneration. In addition, some of thesecompounds can be used as active agents against solid tumors, malignantascites, hematopoietic cancers and hyperproliferative disorders such asthyroid hyperplasia (especially Grave's disease), and cysts (such ashypervascularity of ovarian stroma, characteristic of polycystic ovariansyndrome (Stein-Leventhal syndrome)) since such diseases require aproliferation of blood vessel cells for growth and/or metastasis.

The compounds of the invention can also be used as active agents againstburns, chronic lung disease, stroke, polyps, anaphylaxis, chronic andallergic inflammation, ovarian hyperstimulation syndrome, braintumor-associated cerebral edema, high-altitude, trauma or hypoxiainduced cerebral or pulmonary edema, ocular and macular edema, ascites,and other diseases where vascular hyperpermeability, effusions,exudates, protein extravasation, or edema is a manifestation of thedisease.

The compounds will also be useful in treating disorders in which proteinextravasation leads to the deposition of fibrin and extracellularmatrix, promoting stromal proliferation (e.g. fibrosis, cirrhosis andcarpal tunnel syndrome).

The compounds of the invention are also useful in the treatment ofulcers including bacterial, fungal, Mooren ulcers and ulcerativecolitis.

The compounds of the invention are also useful in the treatment ofconditions wherein undesired angiogenesis, edema, or stromal depositionoccurs in viral infections such as Herpes simplex, Herpes Zoster, AIDS,Kaposi's sarcoma, protozoan infections and toxoplasmosis, followingtrauma, radiation, stroke, endometriosis, ovarian hyperstimulationsyndrome, systemic lupus, sarcoidosis, synovitis, Crohn's disease,sickle cell anemia, Lyme disease, pemphigoid, Paget's disease,hyperviscosity syndrome, Osler-Weber-Rendu disease, chronicinflammation, chronic occlusive pulmonary disease, asthma, andinflammatory rheumatoid or rheumatic disease. The compounds are alsouseful in the reduction of sub-cutaneous fat and for the treatment ofobesity. The compounds of the invention are also useful in the treatmentof ocular conditions such as ocular and macular edema, ocularneovascular disease, scleritis, radial keratotomy, uveitis, vitritis,myopia, optic pits, chronic retinal detachment, post-lasercomplications, glaucoma, conjunctivitis, Stargardt's disease and Ealesdisease in addition to retinopathy and macular degeneration. Thecompounds of the invention are also useful in the treatment ofcardiovascular conditions such as atherosclerosis, restenosis,arteriosclerosis, vascular occlusion and carotid obstructive disease.

The compounds of the invention are also useful in the treatment ofcancer related indications such as solid tumors, sarcomas (especiallyEwing's sarcoma and osteosarcoma), retinoblastoma, rhabdomyosarcomas,neuroblastoma, hematopoietic malignancies, including leukemia andlymphoma, tumor-induced pleural or pericardial effusions, and malignantascites.

The compounds of the invention are also useful in the treatment ofdiabetic conditions such as diabetic retinopathy and microangiopathy.

The compounds of the present invention are also capable of inhibitingother protein kinases, including for example, Src, fgf, c-Met, ron, ckitand ret, and thus may be effective in the treatment of diseasesassociated with other protein kinases. More specifically, the compoundsof the present invention inhibit the Src-family of protein tyrosinekinases such as Lck, Fyn(B), Fyn(T), Lyn, Src, Yes, Hck, Fgr and Blk,and are thus useful in the treatment, including prevention and therapy,of protein tyrosine kinase-associated disorders such as immunologicdisorders. “Protein tyrosine kinase-associated disorders” are thosedisorders which result from aberrant tyrosine kinase activity, and/orwhich are alleviated by the inhibition of one or more of these enzymes.For example, Lck inhibitors are of value in the treatment of a number ofsuch disorders (for example, the treatment of autoimmune diseases), asLck inhibition blocks T cell activation. The treatment of T cellmediated diseases, including inhibition of T cell activation andproliferation, is a preferred embodiment of the present invention.Compounds of the present invention which selectively block T cellactivation and proliferation are preferred. Also, compounds of thepresent invention which may block the activation of endothelial cellprotein tyrosine kinase by oxidative stress, thereby limiting surfaceexpression of adhesion molecules that induce neutrophil binding, andwhich can inhibit protein tyrosine kinase necessary for neutrophilactivation would be useful, for example, in the treatment of ischemiaand reperfusion injury.

The present invention also provides methods for the treatment of proteintyrosine kinase-associated disorders, comprising the step ofadministering to a subject in need thereof at least one compound of theFormula I or of Formula II in an amount effective therefor. Othertherapeutic agents such as those described below may be employed withthe inventive compounds in the present methods. In the methods of thepresent invention, such other therapeutic agent(s) may be administeredprior to, simultaneously with or following the administration of thecompound(s) of the present invention.

Use of the compound(s) of the present invention in treating proteintyrosine kinase-associated disorders is exemplified by, but is notlimited to, treating a range of disorders such as: arthritis (such asrheumatoid arthritis, psoriatic arthritis or osteoarthritis); transplant(such as organ transplant, acute transplant or heterograft or homograft(such as is employed in burn treatment)) rejection; protection fromischemic or reperfusion injury such as ischemic or reperfusion injuryincurred during organ transplantation, myocardial infarction, stroke orother causes; transplantation tolerance induction; multiple sclerosis;inflammatory bowel disease, including ulcerative colitis and Crohn'sdisease; lupus (systemic lupus erythematosis); graft vs. host diseases;T-cell mediated hypersensitivity diseases, including contacthypersensitivity, delayed-type hypersensitivity, and gluten-sensitiveenteropathy (Celiac disease); Type 1 diabetes; psoriasis; contactdermatitis (including that due to poison ivy); Hashimoto's thyroiditis;Sjogren's syndrome; Autoimmune Hyperthyroidism, such as Graves' Disease;Addison's disease (autoimmune disease of the adrenal glands); Autoimmunepolyglandular disease (also known as autoimmune polyglandular syndrome);autoimmune alopecia; pernicious anemia; vitiligo; autoimmunehypopituatarism; Guillain-Barre syndrome; other autoimmune diseases;cancers where Lck or other Src-family kinases such as Src are activatedor overexpressed, such as colon carcinoma and thymoma, or cancers whereSrc-family kinase activity facilitates tumor growth or survival;glomerulonephritis, serum sickness; uticaria; allergic diseases such asrespiratory allergies (asthma, hayfever, allergic rhinitis) or skinallergies; scleracielma; mycosis fungoides; acute inflammatory responses(such as acute respiratory distress syndrome and ishchemia/reperfusioninjury); dermatomyositis; alopecia greata; chronic actinic dermatitis;eczema; Behcet's disease; Pustulosis palmoplanteris; Pyoderma gangrenum;Sezary's syndrome; atopic dermatitis; systemic schlerosis; and morphea.The present invention also provides for a method for treating theaforementioned disorders such as atopic dermatitis by administration ofa therapeutically effective amount of a compound of the presentinvention, which is an inhibitor of protein tyrosine kinase, to apatient in need of such treatment.

Src-family kinases other than Lck, such as Hck and Fgr are important inthe Fcγ receptor induced respiratory burst of neutrophils as well as theFcγ receptor responses of monocytes and macrophages. The compounds ofthe present invention may inhibit the Fcγ induced respiratory burstresponse in neutrophils, and may also inhibit the Fcγ dependentproduction of TNFα. The ability to inhibit Fcγ receptor dependentneutrophil, monocyte and macrophage responses would result in additionalanti-inflammatory activity for the present compounds in additton totheir effects on T cells. This activity would be especially of value,for example, in the treatment of inflammatory diseases, such asarthritis or inflammatory bowel disease.

The present compounds may also be of value for the treatment ofautoimmune glomerulonephritis and other instances of glomerulonephritisinduced by deposition of immune complexes in the kidney that trigger Fcγreceptor responses and which can lead to kidney damage.

In addition, certain Src family kinases, such as Lyn and Fyn(B), may beimportant in the Fcε receptor induced degranulation of mast cells andbasophils that plays an important role in asthma, allergic rhinitis, andother allergic disease. Fcε receptors are stimulated by IgE-antigencomplexes. The compounds of the present invention may inhibit the Fcεinduced degranulation responses. The ability to inhibit Fcε receptordependent mast cell and basophil responses may result in additionalanti-inflammatory activity for the present compounds beyond their effecton T cells.

The combined activity of the present compounds towards monocytes,macrophages, T cells, etc. may prove to be a valuable tool in thetreatment of any of the aforementioned disorders.

In a particular embodiment, the compounds of the present invention areuseful for the treatment of the aforementioned exemplary disordersirrespective of their etiology, for example, for the treatment ofrheumatoid arthritis, transplant rejection, multiple sclerosis,inflammatory bowel disease, lupus, graft v. host disease, T cellmediated hypersensitivity disease, psoriasis, Hashimoto's thyroiditis,Guillain-Barre syndrome, cancer, contact dermatitis, allergic diseasesuch as allergic rhinitis, asthma, ischemic or reperfusion injury, oratopic dermatitis whether or not associated with PTK.

In another embodiment, the compounds are useful for the treatment ofrheumatoid spondylitis, gouty arthritis, adult respiratory distresssyndrome (ARDS), anaphylaxis, muscle degeneration, cachexia, Reiter'ssyndrome, type II diabetes, bone resorption diseases, graft vs. hostreaction, Alzheimer's disease, atherosclerosis, brain trauma, multiplesclerosis, cerebral malaria, sepsis, septic shock, toxic shock syndrome,fever, and myalgias due to infection, or which subject is infected byHIV-1, HIV-2, HIV-3, cytomegalovirus (CMV), influenza, adenovirus, theherpes viruses (including HSV-1, HSV-2), or herpes zoster in a subject,the method comprising administering to the subject a pharmaceuticalcomposition comprising an effective dosage amount of a compound of theinvention.

Besides being useful for human treatment, these compounds are useful forveterinary treatment of companion animals, exotic animals and farmanimals, including mammals, rodents, and the like. For example, animalsincluding horses, dogs, and cats may be treated with compounds providedby the invention.

Formulations and Method of Use

Treatment of diseases and disorders herein is intended to also includetherapeutic administration of a compound of the invention, or apharmaceutical salt thereof, or a pharmaceutical composition of eitherto a subject (i.e., an animal, preferably a mammal, most preferably ahuman) which may be in need of preventative treatment, such as, forexample, for pain, inflammation, cancer and the like. Treatment alsoencompasses prophylactic administration of a compound of the invention,or a pharmaceutical salt thereof, or a pharmaceutical composition ofeither to a subject (i.e., an animal, preferably a mammal, mostpreferably a human). Generally, the subject is initially diagnosed by alicensed physician and/or authorized medical practitioner, and a regimenfor prophylactic and/or therapeutic treatment via administration of thecompound(s) or compositions of the invention is suggested, recommendedor prescribed.

While it may be possible to administer a compound of the inventionalone, in the methods described, the compound administered normally willbe present as an active ingredient in a pharmaceutical composition.Thus, in another embodiment of the invention, there is provided apharmaceutical composition comprising a compound of this invention incombination with a pharmaceutically acceptable carrier, which includesdiluents, excipients, adjuvants and the like (collectively referred toherein as “carrier” materials) as described herein, and, if desired,other active ingredients. A pharmaceutical composition of the inventionmay comprise an effective amount of a compound of the invention or aneffective dosage amount of a compound of the invention. An effectivedosage amount of a compound of the invention includes an amount lessthan, equal to or greater than an effective amount of the compound; forexample, a pharmaceutical composition in which two or more unit dosages,such as in tablets, capsules and the like, are required to administer aneffective amount of the compound, or alternatively, a multi-dosepharmaceutical composition, such as powders, liquids and the like, inwhich an effective amount of the compound is administered byadministering a portion of the composition.

The compound(s) of the present invention may be administered by anysuitable route, preferably in the form of a pharmaceutical compositionadapted to such a route, and in a dose effective for the treatmentintended. The compounds and compositions of the present invention may,for example, be administered orally, mucosally, topically, rectally,pulmonarily such as by inhalation spray, or parentally includingintravascularly, intravenously, intraperitoneally, subcutaneously,intramuscularly intrasternally and infusion techniques, in dosage unitformulations containing conventional pharmaceutically acceptablecarriers, adjuvants, and vehicles.

For oral administration, the pharmaceutical composition may be in theform of, for example, a tablet, capsule, suspension or liquid. Thepharmaceutical composition is preferably made in the form of a dosageunit containing a particular amount of the active ingredient. Examplesof such dosage units are tablets or capsules. For example, these maycontain an amount of active ingredient from about 1 to 2000 mg, andtypically from about 1 to 500 mg. A suitable daily dose for a human orother mammal may vary widely depending on the condition of the patientand other factors, but, once again, can be determined using routinemethods and practices.

The amount of compounds which are administered and the dosage regimenfor treating a disease condition with the compounds and/or compositionsof this invention depends on a variety of factors, including the age,weight, sex and medical condition of the subject, the type of disease,the severity of the disease, the route and frequency of administration,and the particular compound employed. Thus, the dosage regimen may varywidely, but can be determined routinely using standard methods. A dailydose of about 0.01 to 500 mg/kg, advantageously between about 0.01 andabout 50 mg/kg, and more advantageously about 0.01 and about 30 mg/kgbody weight may be appropriate. The daily dose can be administered inone to four doses per day.

For therapeutic purposes, the active compounds of this invention areordinarily combined with one or more adjuvants or “excipients”appropriate to the indicated route of administration. If administered ona per dose basis, the compounds may be admixed with lactose, sucrose,starch powder, cellulose esters of alkanoic acids, cellulose alkylesters, talc, stearic acid, magnesium stearate, magnesium oxide, sodiumand calcium salts of phosphoric and sulfuric acids, gelatin, acacia gum,sodium alginate, polyvinylpyrrolidone, and/or polyvinyl alcohol, to formthe final formulation. For example, the active compound(s) andexcipient(s) may be tableted or encapsulated by known and acceptedmethods for convenient administration. Examples of suitable formulationsinclude, without limitation, pills, tablets, soft and hard-shell gelcapsules, troches, orally-dissolvable forms and delayed orcontrolled-release formulations thereof. Particularly, capsule or tabletformulations may contain one or more controlled-release agents, such ashydroxypropylmethyl cellulose, as a dispersion with the activecompound(s).

In the case of psoriasis and other skin conditions, it may be preferableto apply a topical preparation of compounds of this invention to theaffected area two to four times a day.

Formulations suitable for topical administration include liquid orsemi-liquid preparations suitable for penetration through the skin(e.g., liniments, lotions, ointments, creams, pastes, suspensions andthe like) and drops suitable for administration to the eye, ear, ornose. A suitable topical dose of active ingredient of a compound of theinvention is 0.1 mg to 150 mg administered one to four, preferably oneor two times daily. For topical administration, the active ingredientmay comprise from 0.001% to 10% w/w, e.g., from 1% to 2% by weight ofthe formulation, although it may comprise as much as 10% w/w, butpreferably not more than 5% w/w, and more preferably from 0.1% to 1% ofthe formulation.

When formulated in an ointment, the active ingredients may be employedwith either paraffinic or a water-miscible ointment base. Alternatively,the active ingredients may be formulated in a cream with an oil-in-watercream base. If desired, the aqueous phase of the cream base may include,for example at least 30% w/w of a polyhydric alcohol such as propyleneglycol, butane-1,3-diol, mannitol, sorbitol, glycerol, polyethyleneglycol and mixtures thereof. The topical formulation may desirablyinclude a compound, which enhances absorption or penetration of theactive ingredient through the skin or other affected areas. Examples ofsuch dermal penetration enhancers include DMSO and related analogs.

The compounds of this invention can also be administered by transdermaldevice. Preferably transdermal administration will be accomplished usinga patch either of the reservoir and porous membrane type or of a solidmatrix variety. In either case, the active agent is deliveredcontinuously from the reservoir or microcapsules through a membrane intothe active agent permeable adhesive, which is in contact with the skinor mucosa of the recipient. If the active agent is absorbed through theskin, a controlled and predetermined flow of the active agent isadministered to the recipient. In the case of microcapsules, theencapsulating agent may also function as the membrane.

The oily phase of the emulsions of this invention may be constitutedfrom known ingredients in a known manner. While the phase may comprisemerely an emulsifier, it may comprise a mixture of at least oneemulsifier with a fat or an oil or with both a fat and an oil.Preferably, a hydrophilic emulsifier is included together with alipophilic emulsifier which acts as a stabilizer. It is also preferredto include both an oil and a fat. Together, the emulsifier(s) with orwithout stabilizer(s) make-up the so-called emulsifying wax, and the waxtogether with the oil and fat make up the so-called emulsifying ointmentbase, which forms the oily dispersed phase of the cream formulations.Emulsifiers and emulsion stabilizers suitable for use in the formulationof the present invention include, for example, Tween 60, Span 80,cetostearyl alcohol, myristyl alcohol, glyceryl monostearate, sodiumlauryl sulfate, glyceryl distearate alone or with a wax, or othermaterials well known in the art.

The choice of suitable oils or fats for the formulation is based onachieving the desired cosmetic properties, since the solubility of theactive compound in most oils likely to be used in pharmaceuticalemulsion formulations is very low. Thus, the cream should preferably bea non-greasy, non-staining and washable product with suitableconsistency to avoid leakage from tubes or other containers. Straight orbranched chain, mono- or dibasic alkyl esters such as di-isoadipate,isocetyl stearate, propylene glycol diester of coconut fatty acids,isopropyl myristate, decyl oleate, isopropyl palmitate, butyl stearate,2-ethylhexyl palmitate or a blend of branched chain esters may be used.These may be used alone or in combination depending on the propertiesrequired. Alternatively, high melting point lipids such as white softparaffin and/or liquid paraffin or other mineral oils can be used.

Formulations suitable for topical administration to the eye also includeeye drops wherein the active ingredients are dissolved or suspended insuitable carrier, especially an aqueous solvent for the activeingredients. The active ingredients are preferably present in suchformulations in a concentration of 0.5 to 20%, advantageously 0.5 to 10%and particularly about 1.5% w/w.

Formulations for parenteral administration may be in the form of aqueousor non-aqueous isotonic sterile injection solutions or suspensions.These solutions and suspensions may be prepared from sterile powders orgranules using one or more of the carriers or diluents mentioned for usein the formulations for oral administration or by using other suitabledispersing or wetting agents and suspending agents. The compounds may bedissolved in water, polyethylene glycol, propylene glycol, ethanol, cornoil, cottonseed oil, peanut oil, sesame oil, benzyl alcohol, sodiumchloride, tragacanth gum, and/or various buffers. Other adjuvants andmodes of administration are well and widely known in the pharmaceuticalart. The active ingredient may also be administered by injection as acomposition with suitable carriers including saline, dextrose, or water,or with cyclodextrin (ie. Captisol), cosolvent solubilization (ie.propylene glycol) or micellar solubilization (ie. Tween 80).

The sterile injectable preparation may also be a sterile injectablesolution or suspension in a non-toxic parenterally acceptable diluent orsolvent, for example as a solution in 1,3-butanediol. Among theacceptable vehicles and solvents that may be employed are water,Ringer's solution, and isotonic sodium chloride solution. In addition,sterile, fixed oils are conventionally employed as a solvent orsuspending medium. For this purpose any bland fixed oil may be employed,including synthetic mono- or diglycerides. In addition, fatty acids suchas oleic acid find use in the preparation of injectables. The activeingredient may also be administered by injection as a composition withsuitable carriers including saline, dextrose, or water. The dailyparenteral dosage regimen will be from about 0.1 to about 30 mg/kg oftotal body weight, preferably from about 0.1 to about 10 mg/kg, and morepreferably from about 0.25 mg to 1 mg/kg.

For pulmonary administration, the pharmaceutical composition may beadministered in the form of an aerosol or with an inhaler including drypowder aerosol.

Suppositories for rectal administration of the drug can be prepared bymixing the drug with a suitable non-irritating excipient such as cocoabutter and polyethylene glycols that are solid at ordinary temperaturesbut liquid at the rectal temperature and will therefore melt in therectum and release the drug.

The pharmaceutical compositions may be subjected to conventionalpharmaceutical operations such as sterilization and/or may containconventional adjuvants, such as preservatives, stabilizers, wettingagents, emulsifiers, buffers etc. Tablets and pills can additionally beprepared with enteric coatings. Such compositions may also compriseadjuvants, such as wetting, sweetening, flavoring, and perfuming agents.

Combinations

While the compounds of the invention can be dosed or administered as thesole active pharmaceutical agent, they can also be used in combinationwith one or more compounds of the invention or in conjunction with otheragents. When administered as a combination, the therapeutic agents canbe formulated as separate compositions that are administeredsimultaneously or sequentially at different times, or the therapeuticagents can be given as a single composition.

The phrase “co-therapy” (or “combination-therapy”), in defining use of acompound of the present invention and another pharmaceutical agent, isintended to embrace administration of each agent in a sequential mannerin a regimen that will provide beneficial effects of the drugcombination, and is intended as well to embrace co-administration ofthese agents in a substantially simultaneous manner, such as in a singlecapsule having a fixed ratio of these active agents or in multiple,separate capsules for each agent.

Specifically, the administration of compounds of the present inventionmay be in conjunction with additional therapies known to those skilledin the art in the prevention or treatment of neoplasia, such as withradiation therapy or with cytostatic or cytotoxic agents.

If formulated as a fixed dose, such combination products employ thecompounds of this invention within the accepted dosage ranges. Compoundsof Formulas I-III may also be administered sequentially with knownanticancer or cytotoxic agents when a combination formulation isinappropriate. The invention is not limited in the sequence ofadministration; compounds of the invention may be administered eitherprior to, simultaneous with or after administration of the knownanticancer or cytotoxic agent.

Currently, standard treatment of primary tumors consists of surgicalexcision followed by either radiation or IV administered chemotherapy.The typical chemotherapy regime consists of either DNA alkylatingagents, DNA intercalating agents, CDK inhibitors, or microtubulepoisons. The chemotherapy doses used are just below the maximaltolerated dose and therefore dose limiting toxicities typically include,nausea, vomiting, diarrhea, hair loss, neutropenia and the like.

There are large numbers of antineoplastic agents available in commercialuse, in clinical evaluation and in pre-clinical development, which wouldbe selected for treatment of neoplasia by combination drug chemotherapy.Such antineoplastic agents fall into several major categories, namely,antibiotic-type agents, alkylating agents, antimetabolite agents,hormonal agents, immunological agents, interferon-type agents and acategory of miscellaneous agents.

A first family of antineoplastic agents, which may be used incombination with compounds of the invention consists ofantimetabolite-type/thymidilate synthase inhibitor antineoplasticagents. Suitable antimetabolite antineoplastic agents may be selectedfrom but not limited to the group consisting of 5-FU-fibrinogen,acanthifolic acid, aminothiadiazole, brequinar sodium, carmofur,Ciba-Geigy CGP-30694, cyclopentyl cytosine, cytarabine phosphatestearate, cytarabine conjugates, Lilly DATHF, Merrel Dow DDFC,dezaguanine, dideoxycytidine, dideoxyguanosine, didox, Yoshitomi DMDC,doxifluridine, Wellcome EHNA, Merck & Co. EX-015, fazarabine,floxuridine, fludarabine phosphate, 5-fluorouracil,N-(2′-furanidyl)-5-fluorouracil, Daiichi Seiyaku FO-152, isopropylpyrrolizine, Lilly LY-188011, Lilly LY-264618, methobenzaprim,methotrexate, Wellcome MZPES, norspermidine, NCI NSC-127716, NCINSC-264880, NCI NSC-39661, NCI NSC-612567, Warner-Lambert PALA,pentostatin, piritrexim, plicamycin, Asahi Chemical PL-AC, TakedaTAC-788, thioguanine, tiazofurin, Erbamont TIF, trimetrexate, tyrosinekinase inhibitors, Taiho UFT and uricytin.

A second family of antineoplastic agents, which may be used incombination with compounds of the invention consists of alkylating-typeantineoplastic agents. Suitable alkylating-type antineoplastic agentsmay be selected from but not limited to the group consisting of Shionogi254-S, aldo-phosphamide analogues, altretamine, anaxirone, BoehringerMannheim BBR-2207, bestrabucil, budotitane, Wakunaga CA-102,carboplatin, carmustine, Chinoin-139, Chinoin-153, chlorambucil,cisplatin, cyclophosphamide, American Cyanamid CL-286558, Sanofi CY-233,cyplatate, Degussa D-19-384, Sumimoto DACHP(Myr)2, diphenylspiromustine,diplatinum cytostatic, Erba distamycin derivatives, Chugai DWA-2114R,ITI E09, elmustine, Erbamont FCE-24517, estramustine phosphate sodium,fotemustine, Unimed G-6-M, Chinoin GYKI-17230, hepsul-fam, ifosfamide,iproplatin, lomustine, mafosfamide, mitolactol, Nippon Kayaku NK-121,NCI NSC-264395, NCI NSC-342215, oxaliplatin, Upjohn PCNU, prednimustine,Proter PTT-119, ranimustine, semustine, SmithKline SK&F-101772, YakultHonsha SN-22, spiromus-tine, Tanabe Seiyaku TA-077, tauromustine,temozolomide, teroxirone, tetraplatin and trimelamol.

A third family of antineoplastic agents which may be used in combinationwith compounds of the invention consists of antibiotic-typeantineoplastic agents. Suitable antibiotic-type antineoplastic agentsmay be selected from but not limited to the group consisting of Taiho4181-A, aclarubicin, actinomycin D, actinoplanone, Erbamont ADR-456,aeroplysinin derivative, Ajinomoto AN-201-II, Ajinomoto AN-3, NipponSoda anisomycins, anthracycline, azino-mycin-A, bisucaberin,Bristol-Myers BL-6859, Bristol-Myers BMY-25067, Bristol-Myers BMY-25551,Bristol-Myers BMY-26605, Bristol-Myers BMY-27557, Bristol-MyersBMY-28438, bleomycin sulfate, bryostatin-1, Taiho C-1027, calichemycin,chromoximycin, dactinomycin, daunorubicin, Kyowa Hakko DC-102, KyowaHakko DC-79, Kyowa Hakko DC-88A, Kyowa Hakko DC89-A1, Kyowa HakkoDC92-B, ditrisarubicin B, Shionogi DOB-41, doxorubicin,doxorubicin-fibrinogen, elsamicin-A, epirubicin, erbstatin, esorubicin,esperamicin-A1, esperamicin-A1b, Erbamont FCE-21954, Fujisawa FK-973,fostriecin, Fujisawa FR-900482, glidobactin, gregatin-A, grincamycin,herbimycin, idarubicin, illudins, kazusamycin, kesarirhodins, KyowaHakko KM-5539, Kirin Brewery KRN-8602, Kyowa Hakko KT-5432, Kyowa HakkoKT-5594, Kyowa Hakko KT-6149, American Cyanamid LL-D49194, Meiji SeikaME 2303, menogaril, mitomycin, mitoxantrone, SmithKline M-TAG,neoenactin, Nippon Kayaku NK-313, Nippon Kayaku NKT-01, SR¹International NSC-357704, oxalysine, oxaunomycin, peplomycin, pilatin,pirarubicin, porothramycin, pyrindanycin A, Tobishi RA-I, rapamycin,rhizoxin, rodorubicin, sibanomicin, siwenmycin, Sumitomo SM-5887, SnowBrand SN-706, Snow Brand SN-07, sorangicin-A, sparsomycin, SSPharmaceutical SS-21020, SS Pharmaceutical SS-7313B, SS PharmaceuticalSS-9816B, steffimycin B, Taiho 4181-2, talisomycin, Takeda TAN-868A,terpentecin, thrazine, tricrozarin A, Upjohn U-73975, Kyowa HakkoUCN-10028A, Fujisawa WF-3405, Yoshitomi Y-25024 and zorubicin.

A fourth family of antineoplastic agents which may be used incombination with compounds of the invention consists of a miscellaneousfamily of antineoplastic agents, including tubulin interacting agents,topoisomerase II inhibitors, topoisomerase I inhibitors and hormonalagents, selected from but not limited to the group consisting ofα-carotene, α-difluoromethyl-arginine, acitretin, Biotec AD-5, KyorinAHC-52, alstonine, amonafide, amphethinile, amsacrine, Angiostat,ankinomycin, anti-neoplaston A10, antineoplaston A2, antineoplaston A3,antineoplaston A5, antineoplaston AS2-1, Henkel APD, aphidicolinglycinate, asparaginase, Avarol, baccharin, batracylin, benfluron,benzotript, Ipsen-Beaufour BIM-23015, bisantrene, Bristol-MyersBMY-40481, Vestar boron-10, bromofosfamide, Wellcome BW-502, WellcomeBW-773, caracemide, carmethizole hydrochloride, Ajinomoto CDAF,chlorsulfaquinoxalone, Chemes CHX-2053, Chemex CHX-100, Warner-LambertCI-921, Warner-Lambert CI-937, Warner-Lambert CI-941, Warner-LambertCI-958, clanfenur, claviridenone, ICN compound 1259, ICN compound 4711,Contracan, Yakult Honsha CPT-11, crisnatol, curaderm, cytochalasin B,cytarabine, cytocytin, Merz D-609, DABIS maleate, dacarbazine,datelliptinium, didemnin-B, dihaematoporphyrin ether, dihydrolenperone,dinaline, distamycin, Toyo Pharmar DM-341, Toyo Pharmar DM-75, DaiichiSeiyaku DN-9693, docetaxel elliprabin, elliptinium acetate, TsumuraEPMTC, the epothilones, ergotamine, etoposide, etretinate, fenretinide,Fujisawa FR-57704, gallium nitrate, genkwadaphnin, Chugai GLA-43, GlaxoGR-63178, grifolan NMF-5N, hexadecylphosphocholine, Green Cross HO-221,homoharringtonine, hydroxyurea, BTG ICRF-187, ilmofosine, isoglutamine,isotretinoin, Otsuka JI-36, Ramot K-477, Otsuak K-76COONa, KurehaChemical K-AM, MECT Corp KI-8110, American Cyanamid L-623, leukoregulin,lonidamine, Lundbeck LU-23-112, Lilly LY-186641, NCI (US) MAP, marycin,Merrel Dow MDL-27048, Medco MEDR-340, merbarone, merocyanlnederivatives, methylanilinoacridine, Molecular Genetics MGI-136,minactivin, mitonafide, mitoquidone mopidamol, motretinide, ZenyakuKogyo MST-16, N-(retinoyl)amino acids, Nisshin Flour Milling N-021,N-acylated-dehydroalanines, nafazatrom, Taisho NCU-190, nocodazolederivative, Normosang, NCI NSC-145813, NCI NSC-361456, NCI NSC-604782,NCI NSC-95580, ocreotide, Ono ONO-112, oquizanocine, Akzo Org-10172,paclitaxel, pancratistatin, pazelliptine, Warner-Lambert PD-111707,Warner-Lambert PD-115934, Warner-Lambert PD-131141, Pierre FabrePE-1001, ICRT peptide D, piroxantrone, polyhaematoporphyrin, polypreicacid, Efamol porphyrin, probimane, procarbazine, proglumide, Invitronprotease nexin I, Tobishi RA-700, razoxane, Sapporo Breweries RBS,restrictin-P, retelliptine, retinoic acid, Rhone-Poulenc RP-49532,Rhone-Poulenc RP-56976, SmithKline SK&F-104864, Sumitomo SM-108, KuraraySMANCS, SeaPharm SP-10094, spatol, spirocyclopropane derivatives,spirogermanium, Unimed, SS Pharmaceutical SS-554, strypoldinone,Stypoldione, Suntory SUN 0237, Suntory SUN 2071, superoxide dismutase,Toyama T-506, Toyama T-680, taxol, Teijin TEI-0303, teniposide,thaliblastine, Eastman Kodak TJB-29, tocotrienol, topotecan, Topostin,Teijin TT-82, Kyowa Hakko UCN-01, Kyowa Hakko UCN-1028, ukrain, EastmanKodak USB-006, vinblastine sulfate, vincristine, vindesine,vinestramide, vinorelbine, vintriptol, vinzolidine, withanolides andYamanouchi YM-534.

Alternatively, the compounds of the invention may also be used inco-therapies with other anti-neoplastic agents, such as acemannan,aclarubicin, aldesleukin, alemtuzumab, alitretinoin, altretamine,amifostine, aminolevulinic acid, amrubicin, amsacrine, anagrelide,anastrozole, ANCER, ancestim, ARGLABIN, arsenic trioxide, BAM 002(Novelos), bexarotene, bicalutamide, broxuridine, capecitabine,celmoleukin, cetrorelix, cladribine, clotrimazole, cytarabine ocfosfate,DA 3030 (Dong-A), daclizumab, denileukin diftitox, deslorelin,dexrazoxane, dilazep, docetaxel, docosanol, doxercalciferol,doxifluridine, doxorubicin, bromocriptine, carmustine, cytarabine,fluorouracil, HIT diclofenac, interferon alfa, daunorubicin,doxorubicin, tretinoin, edelfosine, edrecolomab, eflornithine, emitefur,epirubicin, epoetin beta, etoposide phosphate, exemestane, exisulind,fadrozole, filgrastim, finasteride, fludarabine phosphate, formestane,fotemustine, gallium nitrate, gemcitabine, gemtuzumab zogamicin,gimeracil/oteracil/tegafur combination, glycopine, goserelin,heptaplatin, human chorionic gonadotropin, human fetal alphafetoprotein, ibandronic acid, idarubicin, (imiquimod, interferon alfa,interferon alfa, natural, interferon alfa-2, interferon alfa-2a,interferon alfa-2b, interferon alfa-N1, interferon alfa-n3, interferonalfacon-1, interferon alpha, natural, interferon beta, interferonbeta-1a, interferon beta-1b, interferon gamma, natural interferongamma-1a, interferon gamma-1b, interleukin-1 beta, iobenguane,irinotecan, irsogladine, lanreotide, LC 9018 (Yakult), leflunomide,lenograstim, lentinan sulfate, letrozole, leukocyte alpha interferon,leuprorelin, levamisole+fluorouracil, liarozole, lobaplatin, lonidamine,lovastatin, masoprocol, melarsoprol, metoclopramide, mifepristone,miltefosine, mirimostim, mismatched double stranded RNA, mitoguazone,mitolactol, mitoxantrone, molgramostim, nafarelin, naloxone+pentazocine,nartograstim, nedaplatin, nilutamide, noscapine, novel erythropoiesisstimulating protein, NSC 631570 octreotide, oprelvekin, osaterone,oxaliplatin, paclitaxel, pamidronic acid, pegaspargase, peginterferonalfa-2b, pentosan polysulfate sodium, pentostatin, picibanil,pirarubicin, rabbit antithymocyte polyclonal antibody, polyethyleneglycol interferon alfa-2a, porfimer sodium, raloxifene, raltitrexed,rasburicase, rhenium Re 186 etidronate, RII retinamide, rituximab,romurtide, samarium (153 Sm) lexidronam, sargramostim, sizofiran,sobuzoxane, sonermin, strontium-89 chloride, suramin, tasonermin,tazarotene, tegafur, temoporfin, temozolomide, teniposide,tetrachlorodecaoxide, thalidomide, thymalfasin, thyrotropin alfa,topotecan, toremifene, tositumomab-iodine 131, trastuzumab, treosulfan,tretinoin, trilostane, trimetrexate, triptorelin, tumor necrosis factoralpha, natural, ubenimex, bladder cancer vaccine, Maruyama vaccine,melanoma lysate vaccine, valrubicin, verteporfin, vinorelbine,VIRULIZIN, zinostatin stimalamer, or zoledronic acid; abarelix; AE 941(Aeterna), ambamustine, antisense oligonucleotide, bcl-2 (Genta), APC8015 (Dendreon), cetuximab, decitabine, dexaminoglutethimide,diaziquone, EL 532 (Elan), EM 800 (Endorecherche), eniluracil,etanidazole, fenretinide, filgrastim SD01 (Amgen), fulvestrant,galocitabine, gastrin 17 immunogen, HLA-B7 gene therapy (Vical),granulocyte macrophage colony stimulating factor, histaminedihydrochloride, ibritumomab tiuxetan, ilomastat, IM 862 (Cytran),interleukin-2, iproxifene, LDI 200 (Milkhaus), leridistim, lintuzumab,CA 125 MAb (Biomira), cancer MAb (Japan Pharmaceutical Development),HER-2 and Fc MAb (Medarex), idiotypic 105AD7 MAb (CRC Technology),idiotypic CEA MAb (Trilex), LYM-1-iodine 131 MAb (Techniclone),polymorphic epithelial mucin-yttrium 90 MAb (Antisoma), marimastat,menogaril, mitumomab, motexafin gadolinium, MX 6 (Galderma), nelarabine,nolatrexed, P 30 protein, pegvisomant, pemetrexed, porfiromycin,prinomastat, RL 0903 (Shire), rubitecan, satraplatin, sodiumphenylacetate, sparfosic acid, SRL 172 (SR Pharma), SU 5416 (SUGEN), TA077 (Tanabe), tetrathiomolybdate, thaliblastine, thrombopoietin, tinethyl etiopurpurin, tirapazamine, cancer vaccine (Biomira), melanomavaccine (New York University), melanoma vaccine (Sloan KetteringInstitute), melanoma oncolysate vaccine (New York Medical College),viral melanoma cell lysates vaccine (Royal Newcastle Hospital), orvalspodar.

Alternatively, the compounds of the invention may also be used inco-therapies with other anti-neoplastic agents, such as other kinaseinhibitors including p38 inhibitors and CDK inhibitors, TNF inhibitors,metallomatrix proteases inhibitors (MMP), COX-2 inhibitors includingcelecoxib, rofecoxib, parecoxib, valdecoxib, and etoricoxib, NSAID's,SOD mimics or α_(v)β₃ inhibitors.

The invention also provides processes for making compounds for FormulaI, the method comprising the step of A process of making a compound ofFormula I, the process comprising the step of

reacting a compound of Formula A,

wherein A¹, A², A³, A⁴ and R¹ are as defined in claim 1, with a compoundof Formula B, X—R² wherein X is a halogen selected from bromine andiodine and R² is as defined in claim 1, to form a compound of formula I.

The foregoing description is merely illustrative of the invention and isnot intended to limit the invention to the disclosed compounds,compositions and methods. Variations and changes, which are obvious toone skilled in the art, are intended to be within the scope and natureof the invention, as defined in the appended claims. From the foregoingdescription, one skilled in the art can easily ascertain the essentialcharacteristics of this invention, and without departing from the spiritand scope thereof, can make various changes and modifications of theinvention to adapt it to various usages and conditions. All patents andother publications recited herein are hereby incorporated by referencein their entireties.

1. A compound of Formula I:

or a pharmaceutically acceptable salt, thereof, wherein either each ofA¹ and A⁴, independently, is N, A² is CR⁴ and A³ is CR⁵ or each of A²and A³, independently, is N, A¹ is CR³ and A⁴ is CR⁶; R¹ is NR⁷R⁷,NR⁷R⁸, C(O)R⁷, COOR⁷, C(O)R⁸, COOR⁸, C(O)NR⁷R⁷, NR⁷C(O)R⁷, C(O)NR⁷R⁸,NR⁷C(O)R⁸, S(O)₂NR⁷R⁷, NR⁷S(O)₂R⁷, S(O)₂R⁸, S(O)₂NR⁷R⁸ or NR⁷S(O)₂R⁸; R²is a phenyl, naphthyl, pyridyl, pyrimidinyl, quinolinyl, isoquinolinyl,quinazolinyl, isoquinazolinyl, thiophenyl, imidazolyl, thiazolyl,oxazolyl, isoxazolyl, isothiazolyl, indolyl, benzofuranyl,dihydrobenzofuranyl, benzothiophenyl or benzimidazolyl ring substitutedwith 1-5 substituents of R¹⁶, C(O)R¹⁰, COOR¹⁰, C(O)R¹¹, COOR¹¹,C(O)NR¹⁰R¹⁰, C(O)NR¹⁰R¹¹, NR¹⁰C(O)R¹⁰, NR¹⁰C(O)R¹¹, NR¹⁰C(O)NR¹⁰R¹⁰,NR¹⁰C(O)NR¹⁰R¹¹, S(O)₂NR¹⁰R¹⁰, S(O)₂NR¹⁰R¹¹, NR¹⁰S(O)₂R¹⁰ orNR¹⁰S(O)₂R¹¹, provided that one substituent on R² is C(O)NR¹⁰R¹¹,NR¹⁰C(O)R¹¹, NR¹⁰C(O)NR¹⁰R¹⁰, NR¹⁰C(O)NR¹⁰R¹¹, S(O)₂NR¹⁰R¹⁰,S(O)₂NR¹⁰R¹¹, NR¹⁰S(O)₂R¹⁰ or NR¹⁰S(O)₂R¹¹; R³ is H, halo, haloalkyl,OR⁷, SR⁷ or C₁₋₁₀-alkyl, the C₁₋₁₀-alkyl optionally substituted with 1-3substituents of R⁹; R⁴ is H R⁵ is H R⁶ is H, halo, haloalkyl orC₁₋₁₀-alkyl optionally substituted with 1-3 substituents of R⁹; R⁷ is H,C₁₋₁₀-alkyl, C₂₋₁₀-alkenyl, C₂₋₁₀-alkynyl, C₃₋₁₀-cycloalkyl orC₄₋₁₀-cycloalkenyl, each of the C₁₋₁₀-alkyl, C₂₋₁₀-alkenyl,C₂₋₁₀-alkynyl, C₃₋₁₀-cycloalkyl and C₄₋₁₀-cycloalkenyl optionallycomprising 1-4 heteroatoms selected from N, O and S and optionallysubstituted with 1-5 substituents of NR⁸R⁹, NR⁹R⁹, OR⁸, SR⁸, OR⁹, SR⁹,C(O)R⁸, OC(O)R⁸, COOR⁸, C(O)R⁹, OC(O)R⁹, COOR⁹, C(O)NR⁸R⁹, C(O)NR⁹R⁹,NR⁹C(O)R⁸, NR⁹C(O)R⁹, NR⁹C(O)NR⁸R⁹, NR⁹C(O)NR⁹R⁹, NR⁹(COOR⁸),NR⁹(COOR⁹), OC(O)NR⁸R⁹, OC(O)NR⁹R⁹, S(O)₂R⁸, S(O)₂NR⁸R⁹, S(O)₂R⁹,S(O)₂NR⁹R⁹, NR⁹S(O)₂NR⁸R⁹, NR⁹S(O)₂NR⁹R⁹, NR⁹S(O)₂R⁸, NR⁹S(O)₂R⁹, R⁸ orR⁹; R⁸ is a partially or fully saturated or unsaturated 5-8 memberedmonocyclic, 6-12 membered bicyclic, or 7-14 membered tricyclic ringsystem, said ring system formed of carbon atoms optionally including 1-3heteroatoms if monocyclic, 1-6 heteroatoms if bicyclic, or 1-9heteroatoms if tricyclic, said heteroatoms selected from O, N, or S, andwherein said ring system is optionally substituted independently with1-5 substituents of R⁹, oxo, NR⁹R⁹, OR⁹, SR⁹, C(O)R⁹ or a partially orfully saturated or unsaturated 5-6 membered ring of carbon atomsoptionally including 1-3 heteroatoms selected from O, N, or S, andoptionally substituted independently with 1-5 substituents of R⁹; R⁹ isH, halo, haloalkyl, CN, OH, NO₂, NH₂, acetyl, C₁₋₁₀-alkyl,C₂₋₁₀-alkenyl, C₂₋₁₀-alkynyl, C₃₋₁₀-cycloalkyl, C₄₋₁₀-cycloalkenyl,C₁₋₁₀-alkylamino-, C₁₋₁₀-dialkylamino-, C₁₋₁₀-alkoxyl, C₁₋₁₀-thioalkoxylor a saturated or partially or fully unsaturated 5-8 membered monocyclicor a 6-12 membered bicyclic, said ring system formed of carbon atomsoptionally including 1-3 heteroatoms if monocyclic or 1-6 heteroatoms ifbicyclic, said heteroatoms selected from O, N, or S, wherein each of theC₁₋₁₀-alkyl, C₂₋₁₀-alkenyl, C₂₋₁₀-alkynyl, C₃₋₁₀-cycloalkyl,C₄₋₁₀-cycloalkenyl, C₁₋₁₀-alkylamino-, C₁₋₁₀-dialkylamino-,C₁₋₁₀-alkoxyl, C₁₋₁₀-thioalkoxyl and ring of said ring system isoptionally substituted independently with 1-5 substituents of halo,haloalkyl, CN, NO₂, NH₂, OH, oxo, methyl, methoxyl, ethyl, ethoxyl,propyl, propoxyl, isopropyl, cyclopropyl, butyl, isobutyl, tert-butyl,methylamine, dimethylamine, ethylamine, diethylamine, propylamine,isopropylamine, dipropylamine, diisopropylamine, benzyl or phenyl; R¹⁰is H, halo, haloalkyl, CN, NO₂, C₁₋₁₀-alkyl, C₂₋₁₀-alkenyl,C₂₋₁₀-alkynyl, C₃₋₁₀-cycloalkyl or C₄₋₁₀-cycloalkenyl, each of theC₁₋₁₀-alkyl, C₂₋₁₀-alkenyl, C₂₋₁₀-alkynyl, C₃₋₁₀-cycloalkyl andC₄₋₁₀-cycloalkenyl optionally comprising 1-4 heteroatoms selected fromN, O and S and optionally substituted with 1-5 substituents of R¹¹, R¹²or R¹⁶, NR¹¹R¹², NR¹²R¹², OR¹¹, SR¹¹, OR¹², SR¹², C(O)R¹¹, OC(O)R¹¹,COOR¹¹, C(O)R¹², OC(O)R¹², COOR¹², C(O)NR¹¹R¹², NR¹²C(O)R¹¹,C(O)NR¹²R¹², NR¹²C(O)R¹², NR¹²C(O)NR¹¹R¹², NR¹²C(O)NR¹²R¹²,NR¹²(COOR¹¹), NR¹²(COOR¹²), OC(O)NR¹¹R¹², OC(O)NR¹²R¹², S(O)₂R¹¹,S(O)₂R¹², S(O)₂NR¹¹R¹², S(O)₂NR¹²R¹², NR¹²S(O)₂NR¹¹R¹²,NR¹²S(O)₂NR¹²R¹², NR¹²S(O)₂R¹¹, NR¹²S(O)₂R¹², NR¹²S(O)₂R¹¹ orNR¹²S(O)₂R¹²; R¹¹ is a partially or fully saturated or unsaturated 5-8membered monocyclic, 6-12 membered bicyclic, or 7-14 membered tricyclicring system, said ring system formed of carbon atoms optionallyincluding 1-3 heteroatoms if monocyclic, 1-6 heteroatoms if bicyclic, or1-9 heteroatoms if tricyclic, said heteroatoms selected from O, N, or S,and wherein each ring of said ring system is substituted independentlywith 1-5 substituents of R¹², R¹³, R¹⁴ or R¹⁶; alternatively, R¹⁰ andR¹¹ taken together form a partially or fully saturated or unsaturated5-6 membered ring of carbon atoms optionally including 1-3 heteroatomsselected from O, N, or S, and the ring optionally substitutedindependently with 1-5 substituents of R¹², R¹³, R¹⁴ or R¹⁶; R¹² is H,C₁₋₁₀-alkyl, C₂₋₁₀-alkenyl, C₂₋₁₀-alkynyl, C₃₋₁₀-cycloalkyl,C₄₋₁₀-cycloalkenyl, C₁₋₁₀-alkylamino-, C₁₋₁₀-dialkylamino-,C₁₋₁₀-alkoxyl or C₁₋₁₀-thioalkyl, each of which is optionallysubstituted independently with 1-5 substituents of R¹³, R¹⁴, R¹⁵ or R¹⁶;R¹³ is NR¹⁴R¹⁵, NR¹⁵R¹⁵, OR¹⁴, SR¹⁴, OR¹⁵, SR¹⁵, C(O)R¹⁴, OC(O)R¹⁴,COOR¹⁴, C(O)R¹⁵, OC(O)R¹⁵, COOR¹⁵, C(O)NR¹⁴R¹⁵, C(O)NR¹⁵R¹⁵,NR¹⁴C(O)R¹⁴, NR¹⁵C(O)R¹⁴, NR¹⁴C(O)R¹⁵, NR¹⁵C(O)R¹⁵, NR¹⁵C(O)NR¹⁴R¹⁵,NR¹⁵C(O)NR¹⁵R¹⁵, NR¹⁵(COOR¹⁴), NR¹⁵(COOR¹⁵), OC(O)NR¹⁴R¹⁵, OC(O)NR¹⁵R¹⁵,S(O)₂R¹⁴, S(O)₂R¹⁵, S(O)₂NR¹⁴R¹⁵, S(O)₂NR¹⁵R¹⁵, NR¹⁴S(O)₂NR¹⁴R¹⁵,NR¹⁵S(O)₂NR¹⁵R¹⁵, NR¹⁴S(O)₂R¹⁴ or NR¹⁵S(O)₂R¹⁵; R¹⁴ is a partially orfully saturated or unsaturated 5-8 membered or a saturated or partiallyor fully unsaturated 5-8 membered monocyclic, 6-12 membered bicyclic, or7-14 membered tricyclic ring system, said ring system formed of carbonatoms optionally including 1-3 heteroatoms if monocyclic, 1-6heteroatoms if bicyclic, or 1-9 heteroatoms if tricyclic, saidheteroatoms selected from O, N, or S, and wherein said ring system isoptionally substituted independently with 1-5 substituents of R¹⁵ orR¹⁶; R¹⁵ is H or C₁₋₁₀-alkyl, C₂₋₁₀-alkenyl, C₂₋₁₀-alkynyl,C₃₋₁₀-cycloalkyl, C₄₋₁₀-cycloalkenyl, C₁₋₁₀-alkylamino-,C₁₋₁₀-dialkylamino-, C₁₋₁₀-alkoxyl or C₁₋₁₀-thioalkoxyl, each of whichis optionally substituted independently with 1-5 substituents of R¹⁶;R¹⁶ is H, halo, haloalkyl, CN, OH, NO₂, NH₂, OH, methyl, methoxyl,ethyl, ethoxyl, propyl, propoxyl, isopropyl, cyclopropyl, butyl,isobutyl, tert-butyl, methylamino, dimethylamino, ethylamino,diethylamino, isopropylamino, oxo, acetyl, benzyl, phenyl, cyclopropyl,cyclobutyl or a partially or fully saturated or unsaturated 5-8 memberedmonocyclic or 6-12 membered bicyclic ring system, said ring systemformed of carbon atoms optionally including 1-3 heteroatoms ifmonocyclic or 1-6 heteroatoms if bicyclic, said heteroatoms selectedfrom O, N, or S, and optionally substituted independently with 1-5substituents of halo, haloalkyl, CN, NO₂, NH₂, OH, methyl, methoxyl,ethyl, ethoxyl, propyl, propoxyl, isopropyl, cyclopropyl, butyl,isobutyl, tert-butyl, methylamino, dimethylamino, ethylamino,diethylamino, isopropylamino, benzyl or phenyl; and provided that (1)when said at least one substituent on said R² ring system is C(O)NR¹⁰R¹⁰or C(O)NR¹⁰R¹¹, then R¹⁰ and R¹¹, independently, are not —CH₂-L-Q or—C(C₁₋₆alkyl)(C₁₋₆alkyl)-L-Q, wherein L is —O—, —NH—, —NHC(O)—,—NHC(O)N—, NHC(═NH)N— or —CO₂— and Q is H, substituted or unsubstitutedC₁₋₆alkyl, substituted or unsubstituted aryl, substituted orunsubstituted heterocyclyl, substituted or unsubstituted heteraryl orC₁₋₆alkyl substituted with aryl, heterocyclyl or heteroaryl; or (2) whenR² is a pyrimidyl ring substituted with NR⁷R⁸, then the NR⁷R⁸substitution is not ortho to the alkynyl group of Formula I.
 2. Thecompound of claim 1 wherein each of A² and A³, independently, is N, A¹is CR³ and A⁴ is CR⁶.
 3. The compound of claim 1 wherein each of A¹ andA⁴, independently, is N, A² is CR⁴ and A³ is CR⁵.
 4. The compound ofclaim 3 wherein R² is a phenyl, naphthyl, pyridyl, thiophenyl, indolyl,benzofuranyl, dihydrobenzofuranyl, benzothiophenyl or benzimidazolylring and one of the 1-5 substituents on R² is C(O)NR¹⁰R¹¹, orNR¹⁰C(O)R¹¹.
 5. The compound of claim 1 wherein A¹ and A⁴,independently, are N; A² is CH; A³ is CH; R¹ is NR⁷R⁷, NR⁷R⁸, C(O)R⁷,COOR⁷, C(O)R⁸, COOR⁸, C(O)NR⁷R⁷, NR⁷C(O)R⁷, C(O)NR⁷R⁸, NR⁷C(O)R⁸,S(O)₂NR⁷R⁷, NR⁷S(O)₂R⁷, S(O)₂R⁸, S(O)₂NR⁷R⁸ or NR⁷S(O)₂R⁸; R² is aphenyl, naphthyl, pyridyl, thiophenyl, furyl, pyrrolyl, indolyl,isoindolyl, benzofuranyl, dihydrobenzofuranyl, benzothiophenyl orbenzimidazolyl ring, said ring substituted independently with 1-5substituents of R¹⁶ and one substituent of C(O)NR¹⁰R¹¹, or NR¹⁰C(O)R¹¹;R⁷ is H or C₁₋₁₀-alkyl optionally substituted with 1-3 substituents ofNR⁸R⁹, NR⁹R⁹, OR⁸, SR⁸, OR⁹, SR⁹, C(O)R⁸, OC(O)R⁸, COOR⁸, C(O)R⁹,OC(O)R⁹, COOR⁹, C(O)NR⁸R⁹, C(O)NR⁹R⁹, NR⁹C(O)R⁸, NR⁹C(O)R⁹,NR⁹C(O)NR⁸R⁹, NR⁹C(O)NR⁹R⁹, NR⁹(COOR⁸), NR⁹(COOR⁹), OC(O)NR⁸R⁹,OC(O)NR⁹R⁹, S(O)₂R⁸, S(O)₂NR⁸R⁹, S(O)₂R⁹, S(O)₂NR⁹R⁹, NR⁹S(O)₂NR⁸R⁹,NR⁹S(O)₂NR⁹R⁹, NR⁹S(O)₂R⁸, NR⁹S(O)₂R⁹, R⁸ or R⁹; R⁸ is a partially orfully saturated or unsaturated 5-8 membered monocyclic, 6-12 memberedbicyclic, or 7-14 membered tricyclic ring system, said ring systemformed of carbon atoms optionally including 1-3 heteroatoms ifmonocyclic, 1-6 heteroatoms if bicyclic, or 1-9 heteroatoms iftricyclic, said heteroatoms selected from O, N, or S, and wherein saidring system is optionally substituted independently with 1-5substituents of R⁹, oxo, NR⁹R⁹, OR⁹, SR⁹, C(O)R⁹ or a partially or fullysaturated or unsaturated 5-6 membered ring of carbon atoms optionallyincluding 1-3 heteroatoms selected from O, N, or S, and optionallysubstituted independently with 1-3 substituents of R⁹; R⁹ is H, halo,haloalkyl, CN, OH, NO₂, NH₂, acetyl, C₁₋₁₀-alkyl, C₂₋₁₀-alkenyl,C₂₋₁₀-alkynyl, C₃₋₁₀-cycloalkyl, C₄₋₁₀-cycloalkenyl, C₁₋₁₀-alkylamino-,C₁₋₁₀-dialkylamino-, C₁₋₁₀-alkoxyl, C₁₋₁₀-thioalkoxyl or a saturated orpartially or fully unsaturated 5-8 membered monocyclic or a 6-12membered bicyclic, said ring system formed of carbon atoms optionallyincluding 1-3 heteroatoms if monocyclic or 1-6 heteroatoms if bicyclic,said heteroatoms selected from O, N, or S, wherein each of theC₁₋₁₀-alkyl, C₂₋₁₀-alkenyl, C₂₋₁₀-alkynyl, C₃₋₁₀-cycloalkyl,C₄₋₁₀-cycloalkenyl, C₁₋₁₀-alkylamino-, C₁₋₁₀-dialkylamino-,C₁₋₁₀-alkoxyl, C₁₋₁₀-thioalkoxyl and ring of said ring system isoptionally substituted independently with 1-3 substituents of halo,haloalkyl, CN, NO₂, NH₂, OH, oxo, methyl, methoxyl, ethyl, ethoxyl,propyl, propoxyl, isopropyl, cyclopropyl, butyl, isobutyl, tert-butyl,methylamine, dimethylamine, ethylamine, diethylamine, propylamine,isopropylamine, dipropylamine, diisopropylamine, benzyl or phenyl; R¹⁰is H, halo, haloalkyl, CN, NO₂, C₁₋₁₀-alkyl or C₃₋₁₀-cycloalkyl, each ofthe C₁₋₁₀-alkyl and C₃₋₁₀-cycloalkyl optionally substituted with 1-5substituents of R¹⁶, NR¹¹R¹², NR¹²R¹², OR¹¹, SR¹¹, OR¹², SR¹², C(O)R¹¹,OC(O)R¹¹, COOR¹¹, C(O)R¹², OC(O)R¹², COOR¹², C(O)NR¹¹R¹², NR¹²C(O)R¹¹,C(O)NR¹²R¹², NR¹²C(O)R¹², NR¹²C(O)NR¹¹R¹², NR¹²C(O)NR¹²R¹²,NR¹²(COOR¹¹), NR¹²(COOR¹²), C(O)NR¹¹R¹², OC(O)NR¹²R¹², S(O)₂R¹¹,S(O)₂R¹², S(O)₂NR¹¹R¹², S(O)₂NR¹²R¹², NR¹²S(O)₂NR¹¹R¹²,NR¹²S(O)₂NR¹²R¹², NR¹²S(O)₂R¹¹, NR¹²S(O)₂R¹², NR¹²S(O)₂R¹¹ orNR¹²S(O)₂R¹²; R¹¹ is a partially or fully saturated or unsaturated 5-8membered monocyclic, or 6-12 membered bicyclic ring system, said ringsystem formed of carbon atoms optionally including 1-3 heteroatoms ifmonocyclic or 1-6 heteroatoms if bicyclic, said heteroatoms selectedfrom O, N, or S, and wherein each ring of said ring system issubstituted independently with 1-5 substituents of R¹², R¹³, R¹⁴ or R¹⁶;alternatively, R¹⁰ and R¹¹ taken together form a partially or fullysaturated or unsaturated 5-6 membered ring of carbon atoms optionallyincluding 1-3 heteroatoms selected from O, N, or S, and the ringoptionally substituted independently with 1-5 substituents of R¹², R¹³,R¹⁴ or R¹⁶; R¹² is H, C₁₋₁₀-alkyl, C₂₋₁₀-alkenyl, C₂₋₁₀-alkynyl,C₃₋₁₀-cycloalkyl, C₄₋₁₀-cycloalkenyl, C₁₋₁₀-alkylamino-,C₁₋₁₀-dialkylamino-, C₁₋₁₀-alkoxyl or C₁₋₁₀-thioalkyl, each of which isoptionally substituted independently with 1-5 substituents of R¹³, R¹⁴,R¹⁵ or R¹⁶; R¹³ is NR¹⁴R¹⁵, NR¹⁵R¹⁵, OR¹⁴, SR¹⁴, OR¹⁵; SR¹⁵, C(O)R¹⁴,OC(O)R¹⁴, COOR¹⁴, C(O)R¹⁵, OC(O)R¹⁵, COOR¹⁵, C(O)NR¹⁴R¹⁵, C(O)NR¹⁵R¹⁵,NR¹⁴C(O)R¹⁴, NR¹⁵C(O)R¹⁴, NR¹⁴C(O)R¹⁵, NR¹⁵C(O)R¹⁵, NR¹⁵C(O)NR¹⁴R¹⁵,NR¹⁵C(O)NR¹⁵R¹⁵, NR¹⁵(COOR¹⁴), NR¹⁵(COOR¹⁵), OC(O)NR¹⁴R¹⁵, OC(O)NR¹⁵R¹⁵,S(O)₂R¹⁴, S(O)₂R¹⁵, S(O)₂NR¹⁴R¹⁵, S(O)₂NR¹⁵R¹⁵, NR¹⁴S(O)₂NR¹⁴R¹⁵,NR¹⁵S(O)₂NR¹⁵R¹⁵, NR¹⁴S(O)₂R¹⁴ or NR¹⁵S(O)₂R¹⁵; R¹⁴ is a partially orfully saturated or unsaturated 5-8 membered or a saturated or partiallyor fully unsaturated 5-8 membered monocyclic, 6-12 membered bicyclic, or7-14 membered tricyclic ring system, said ring system formed of carbonatoms optionally including 1-3 heteroatoms if monocyclic, 1-6heteroatoms if bicyclic, or 1-9 heteroatoms if tricyclic, saidheteroatoms selected from O, N, or S, and wherein each ring of said ringsystem is optionally substituted independently with 1-5 substituents ofR¹⁵ or R¹⁶; R¹⁵ is H or C₁₋₁₀-alkyl, C₂₋₁₀-alkenyl, C₂₋₁₀-alkynyl,C₃₋₁₀-cycloalkyl, C₄₋₁₀-cycloalkenyl, C₁₋₁₀-alkylamino-,C₁₋₁₀-dialkylamino-, C₁₋₁₀-alkoxyl or C₁₋₁₀-thioalkoxyl, each of whichis optionally substituted independently with 1-5 substituents of R¹⁶;R¹⁶ is H, halo, haloalkyl, CN, OH, NO₂, NH₂, OH, methyl, methoxyl,ethyl, ethoxyl, propyl, propoxyl, isopropyl, cyclopropyl, butyl,isobutyl, tert-butyl, methylamino, dimethylamino, ethylamino,diethylamino, isopropylamino, oxo, acetyl, benzyl, phenyl, cyclopropyl,cyclobutyl or a partially or fully saturated or unsaturated 5-8 memberedmonocyclic or 6-12 membered bicyclic ring system, said ring systemformed of carbon atoms optionally including 1-3 heteroatoms ifmonocyclic or 1-6 heteroatoms if bicyclic, said heteroatoms selectedfrom O, N, or S, and optionally substituted independently with 1-5substituents of halo, haloalkyl, CN, NO₂, NH₂, OH, methyl, methoxyl,ethyl, ethoxyl, propyl, propoxyl, isopropyl, cyclopropyl, butyl,isobutyl, tert-butyl, methylamino, dimethylamino, ethylamino,diethylamino, isopropylamino, benzyl or phenyl; and provided that (1)when said at least one substituent on said R² ring system is C(O)NR¹⁰R¹⁰or C(O)NR¹⁰R¹¹, then R¹⁰ and R¹¹, independently, are not —CH₂-L-Q or—C(C₁₋₆alkyl)(C₁₋₆alkyl)-L-Q, wherein L is —O—, —NH—, —NHC(O)—,—NHC(O)N—, NHC(═NH)N— or —CO₂— and Q is H, substituted or unsubstitutedC₁₋₆alkyl, substituted or unsubstituted aryl, substituted orunsubstituted heterocyclyl, substituted or unsubstituted heteraryl orC₁₋₆alkyl substituted with aryl, heterocyclyl or heteroaryl.
 6. Thecompound of claim 1, having a general Formula II

wherein R² is

wherein each of A⁵, A⁶, and A⁷ is, independently, CR^(3b) or N; A⁸ isCR^(3c) or N; and A⁹ is CR^(3d) or N, provided no more than two of A⁵,A⁶, A⁷, A⁸ and A⁹ is N; Y¹ is O or S; Y² is NR^(3a); R^(3a) isC(O)NR¹⁰R¹¹, NR¹⁰C(O)R¹¹, NR¹⁰C(O)NR¹⁰R¹⁰ or NR¹⁰C(O)NR¹⁰R¹¹; R^(3b) isH, halo, haloalkyl, CN, NO₂, NH₂, C₁₋₁₀-alkyl, C₂₋₁₀-alkenyl,C₂₋₁₀-alkynyl or C₃₋₁₀-cycloalkyl; R^(3c) is H, halo, haloalkyl, CN,NO₂, NH₂, C₁₋₁₀-alkyl, C₂₋₁₀-alkenyl, C₂₋₁₀-alkynyl or C₃₋₁₀-cycloalkyl;R^(3d) is H, halo, haloalkyl, CN, NO₂, NH₂, C₁₋₁₀-alkyl, C₂₋₁₀-alkenyl,C₂₋₁₀-alkynyl or C₃₋₁₀-cycloalkyl; and alternatively, R^(3c) and R^(3d)taken together with the atoms to which they are attached form a phenylor tetrahydrofuranyl ring system, optionally substituted with 1-3substituents of halo, haloalkyl, CN, NO₂, NH₂, C₁₋₁₀-alkyl,C₂₋₁₀-alkenyl, C₂₋₁₀-alkynyl or C₃₋₁₀-cycloalkyl, provided that whenR^(3a) is NR¹⁰C(O)NR¹⁰R¹⁰ or NR¹⁰C(O)NR¹⁰R¹¹, then R² is

R⁴ is H; R⁵ is H; R⁷ is H, C₁₋₁₀-alkyl, C₂₋₁₀-alkenyl, C₂₋₁₀-alkynyl,C₃₋₁₀-cycloalkyl or C₄₋₁₀-cycloalkenyl, each of the C₁₋₁₀-alkyl,C₂₋₁₀-alkenyl, C₂₋₁₀-alkynyl, C₃₋₁₀-cycloalkyl and C₄₋₁₀-cycloalkenyloptionally comprising 1-4 heteroatoms selected from N, O and S andoptionally substituted with 1-5 substituents of NR⁸R⁹, NR⁹R⁹, OR⁸, SR⁸,OR⁹, SR⁹, C(O)R⁸, OC(O)R⁸, COOR⁸, C(O)R⁹, OC(O)R⁹, COOR⁹, C(O)NR⁸R⁹,C(O)NR⁹R⁹, NR⁹C(O)R⁸, NR⁹C(O)R⁹, NR⁹C(O)NR⁸R⁹, NR⁹C(O)NR⁹R⁹, NR⁹(COOR⁸),NR⁹(COOR⁹), OC(O)NR⁸R⁹, OC(O)NR⁹R⁹, S(O)₂R⁸, S(O)₂NR⁸R⁹, S(O)₂R⁹,S(O)₂NR⁹R⁹, NR⁹S(O)₂NR⁸R⁹, NR⁹S(O)₂NR⁹R⁹, NR⁹S(O)₂R⁸, NR⁹S(O)₂R⁹, R⁸ orR⁹; R⁸ is a phenyl, naphthyl, pyridyl, piperazinyl, triazinyl,quinolinyl, isoquinolinyl, quinazolinyl, isoquinazolinyl, thiophenyl,furyl, pyrrolyl, imidazolyl, triazolyl, thiazolyl, oxazolyl, isoxazolyl,isothiazolyl, indolyl, isoindolyl, benzofuranyl, benzothiophenyl,benzimidazolyl, tetrahydrofuranyl, pyrrolidinyl, oxazolinyl,isoxazolinyl, thiazolinyl, pyrazolinyl, morpholinyl, piperidinyl,piperazinyl, pyranyl, dioxozinyl, cyclopropyl, cyclobutyl, cyclopentyl,cyclohexyl or cycloheptyl ring system, said ring system optionallysubstituted independently with 1-3 substituents of R⁹, oxo, NR⁹R⁹, OR⁹;SR⁹, C(O)R⁹, phenyl, pyridyl, piperidyl, piperazinyl or morpholinyl; R⁹is H, halo, haloalkyl, CN, OH, NO₂, NH₂, acetyl, C₁₋₁₀-alkyl,C₂₋₁₀-alkenyl, C₂₋₁₀-alkynyl, C₃₋₁₀-cycloalkyl, C₁₋₁₀-alkylamino-,C₁₋₁₀-dialkylamino-, C₁₋₁₀-alkoxyl, C₁₋₁₀-thioalkoxyl or a ring systemselected from phenyl, naphthyl, pyridyl, piperazinyl, triazinyl,quinolinyl, isoquinolinyl, quinazolinyl, isoquinazolinyl, thiophenyl,furyl, pyrrolyl, imidazolyl, triazolyl, thiazolyl, oxazolyl, isoxazolyl,isothiazolyl, indolyl, isoindolyl, benzofuranyl, benzothiophenyl,benzimidazolyl, tetrahydrofuranyl, pyrrolidinyl, oxazolinyl,isoxazolinyl, thiazolinyl, pyrazolinyl, morpholinyl, piperidinyl,piperazinyl, pyranyl and dioxozinyl, each of the C₁₋₁₀-alkyl,C₂₋₁₀-alkenyl, C₂₋₁₀-alkynyl, C₃₋₁₀-cycloalkyl, C₁₋₁₀-alkylamino-,C₁₋₁₀-dialkylamino-, C₁₋₁₀-alkoxyl, C₁₋₁₀-thioalkoxyl and ring systemoptionally substituted independently with 1-3 substituents of halo,haloalkyl, CN, NO₂, NH₂, OH, oxo, methyl, methoxyl, ethyl, ethoxyl,propyl, propoxyl, isopropyl, cyclopropyl, butyl, isobutyl, tert-butyl,methylamino, dimethylamino, ethylamino, diethylamino, propylamine,isopropylamine, dipropylamine, diisopropylamine, benzyl or phenyl; R¹⁰is H, halo, haloalkyl, CN, NO₂, C₁₋₁₀-alkyl, C₂₋₁₀-alkenyl,C₂₋₁₀-alkynyl, C₃₋₁₀-cycloalkyl or C₄₋₁₀-cycloalkenyl, each of theC₁₋₁₀-alkyl, C₂₋₁₀-alkenyl, C₂₋₁₀-alkynyl, C₃₋₁₀-cycloalkyl andC₄₋₁₀-cycloalkenyl optionally comprising 1-4 heteroatoms selected fromN, O and S and optionally substituted with one or more substituents ofR¹¹, R¹² or R¹⁶, NR¹¹R¹², NR¹²R¹², OR¹¹, SR¹¹, OR¹², SR¹², C(O)R¹¹,OC(O)R¹¹, COOR¹¹, C(O)R¹², OC(O)R¹², COOR¹², C(O)NR¹¹R¹², NR¹²C(O)R¹¹,C(O)NR¹²R¹², NR¹²C(O)R¹², NR¹²C(O)NR¹¹R¹², NR¹²C(O)NR¹²R¹²,NR¹²(COOR¹¹), NR¹²(COOR¹²), OC(O)NR¹¹R¹², OC(O)NR¹²R¹², S(O)₂R¹¹,S(O)₂R¹², S(O)₂NR¹¹R¹², S(O)₂NR¹²R¹², NR¹²S(O)₂NR¹¹R¹²,NR¹²S(O)₂NR¹²R¹², NR¹²S(O)₂R¹¹, NR¹²S(O)₂R¹², NR¹²S(O)₂R¹¹ orNR¹²S(O)₂R¹²; R¹¹ is a phenyl, naphthyl, 5,6,7,8-tetrahydronaphthyl,dihydro-indenyl, pyridyl, pyrimidinyl, triazinyl, quinolinyl,tetrahydroquinolinyl, oxo-tetrahydroquinolinyl, isoquinolinyl,oxo-tetrahydroisoquinolinyl, tetrahydroisoquinolinyl, quinazolinyl,isoquinazolinyl, thiophenyl, furyl, tetrahydrofuranyl, pyrrolyl,pyrazolyl, thieno-pyrazolyl, tetrahydropentapyrazolyl, imidazolyl,triazolyl, tetrazolyl, thiazolyl, thiadiazolyl, benzothiazolyl,oxazolyl, oxadiazolyl, benzoxazolyl, benzoxadiazolyl, isoxazolyl,isothiazolyl, indolyl, azaindolyl, 2,3-dihydroindolyl, isoindolyl,indazolyl, benzofuranyl, benzothiophenyl, benzimidazolyl,imidazo-pyridinyl, purinyl, benzotriazolyl, oxazolinyl, isoxazolinyl,thiazolinyl, pyrrolidinyl, pyrazolinyl, morpholinyl, piperidinyl,piperazinyl, pyranyl, dioxozinyl, 2,3-dihydro-1,4-benzoxazinyl,1,3-benzodioxolyl, cyclopropyl, cyclobutyl, azetidinyl, cyclopentyl,cyclohexyl or cycloheptyl ring system, said ring system substitutedindependently with 1-3 substituents of R¹², R¹³, R¹⁴ or R¹⁶;alternatively, R¹⁰ and R¹¹ taken together form a partially or fullysaturated or unsaturated 5-6 membered ring of carbon atoms optionallyincluding 1-3 heteroatoms selected from O, N, or S, and the ringoptionally substituted independently with 1-3 substituents of R¹², R¹³,R¹⁴ or R¹⁶; R¹² is H, C₁₋₁₀-alkyl, C₂₋₁₀-alkenyl, C₂₋₁₀-alkynyl,C₃₋₁₀-cycloalkyl, C₄₋₁₀-cycloalkenyl, C₁₋₁₀-alkylamino-,C₁₋₁₀-dialkylamino-, C₁₋₁₀-alkoxyl or C₁₋₁₀-thioalkyl, each of which isoptionally substituted independently with 1-3 substituents of R¹³, R¹⁴,R¹⁵ or R¹⁶; R¹³ is NR¹⁴R¹⁵, NR¹⁵R¹⁵, OR¹⁴; SR¹⁴, OR¹⁵; SR¹⁵, C(O)R¹⁴,OC(O)R¹⁴, COOR¹⁴, C(O)R¹⁵, OC(O)R¹⁵, COOR¹⁵, C(O)NR¹⁴R¹⁵, C(O)NR¹⁵R¹⁵,NR¹⁴C(O)R¹⁴, NR¹⁵C(O)R¹⁴, NR¹⁴C(O)R¹⁵, NR¹⁵C(O)R¹⁵, NR¹⁵C(O)NR¹⁴R¹⁵,NR¹⁵C(O)NR¹⁵R¹⁵, NR¹⁵(COOR¹⁴), NR¹⁵(COOR¹⁵), OC(O)NR¹⁴R¹⁵, OC(O)NR¹⁵R¹⁵,S(O)₂R¹⁴, S(O)₂R¹⁵, S(O)₂NR¹⁴R¹⁵, S(O)₂NR¹⁵R¹⁵, NR¹⁴S(O)₂NR¹⁴R¹⁵,NR¹⁵S(O)₂NR¹⁵R¹⁵, NR¹⁴S(O)₂R¹⁴ or NR¹⁵S(O)₂R¹⁵; R¹⁴ is phenyl, pyridyl,pyrimidinyl, thiophenyl, furyl, tetrahydrofuryl, pyrrolyl, pyrazolyl,thieno-pyrazolyl, imidazolyl, triazolyl, thiazolyl, thiadiazolyl,benzothiazolyl, oxazolyl, oxadiazolyl, benzoxazolyl, benzoxadiazolyl,isoxazolyl, isothiazolyl, indolyl, azaindolyl, isoindolyl, indazolyl,benzofuranyl, benzothiophenyl, benzimidazolyl, pyrrolidinyl,pyrazolinyl, morpholinyl, piperidinyl, piperazinyl,2,3-dihydro-1,4-benzoxazinyl, 1,3-benzodioxolyl, cyclopropyl,cyclobutyl, azetidinyl, cyclopentyl and cyclohexyl, each of which isoptionally substituted independently with 1-3 substituents of R¹⁵ orR¹⁶; R¹⁵ is H or C₁₋₁₀-alkyl, C₂₋₁₀-alkenyl, C₂₋₁₀-alkynyl,C₃₋₁₀-cycloalkyl, C₄₋₁₀-cycloalkenyl, C₁₋₁₀-alkylamino-,C₁₋₁₀-dialkylamino-, C₁₋₁₀-alkoxyl or C₁₋₁₀-thioalkoxyl, each of whichis optionally substituted independently with 1-5 substituents of R¹⁶;and R¹⁶ is H, halo, haloalkyl, CN, OH, NO₂, NH₂, OH, methyl, methoxyl,ethyl, ethoxyl, propyl, propoxyl, isopropyl, cyclopropyl, butyl,isobutyl, tert-butyl, methylamino, dimethylamino, ethylamino,diethylamino, isopropylamino, oxo, acetyl, benzyl, phenyl, cyclopropyl,cyclobutyl or a partially or fully saturated or unsaturated 5-8 memberedmonocyclic or 6-12 membered bicyclic ring system, said ring systemformed of carbon atoms optionally including 1-3 heteroatoms ifmonocyclic or 1-6 heteroatoms if bicyclic, said heteroatoms selectedfrom O, N, or S, and optionally substituted independently with 1-5substituents of halo, haloalkyl, CN, NO₂, NH₂, OH, methyl, methoxyl,ethyl, ethoxyl, propyl, propoxyl, isopropyl, cyclopropyl, butyl,isobutyl, tert-butyl, methylamino, dimethylamino, ethylamino,diethylamino, isopropylamino, benzyl or phenyl.
 7. The compound of claim6 wherein R² is

wherein R^(3a) is C(O)NR¹⁰R¹¹, or NR¹⁰C(O)R¹¹; each of R^(3b), R^(3c)and R^(3d), independently, is H, F, Cl, Br, I, CF₃, CF₂CF₃, OCF₃,OCF₂CF₃, CN, NO₂, NH₂, methyl, ethyl, propyl, isopropyl, n-butyl,sec-butyl, tert-butyl, acetylenyl, cyclopropyl, cyclobutyl, cyclopentyl,cyclohexyl, OH, methoxyl, ethoxyl, propoxyl, SH, thiomethyl orthioethyl; each of R⁴ and R⁵, independently, is H or methyl; each R⁷,independently, is H or C₁₋₁₀-alkyl; R¹⁰ is H, methyl, ethyl, propyl,isopropyl, n-butyl, sec-butyl, tert-butyl, acetylenyl, cyclopropyl,cyclobutyl, cyclopentyl, cyclohexyl, OH, methoxyl, ethoxyl, propoxyl,SH, thiomethyl or thioethyl; each of which is optionally substitutedwith one or more substituents of R¹¹, R¹² or R¹⁶; R¹¹ is a phenyl,naphthyl, 5,6,7,8-tetrahydronaphthyl, dihydro-indenyl, pyridyl,pyrimidinyl, triazinyl, quinolinyl, tetrahydroquinolinyl,oxo-tetrahydroquinolinyl, isoquinolinyl, oxo-tetrahydroisoquinolinyl,tetrahydroisoquinolinyl, quinazolinyl, isoquinazolinyl, thiophenyl,furyl, tetrahydrofuranyl, pyrrolyl, pyrazolyl, thieno-pyrazolyl,tetrahydropentapyrazolyl, imidazolyl, triazolyl, tetrazolyl, thiazolyl,thiadiazolyl, benzothiazolyl, oxazolyl, oxadiazolyl, benzoxazolyl,benzoxadiazolyl, isoxazolyl, isothiazolyl, indolyl, azaindolyl,2,3-dihydroindolyl, isoindolyl, indazolyl, benzofuranyl,benzothiophenyl, benzimidazolyl, imidazo-pyridinyl, purinyl,benzotriazolyl, oxazolinyl, isoxazolinyl, thiazolinyl, pyrrolidinyl,pyrazolinyl, morpholinyl, piperidinyl, piperazinyl, pyranyl, dioxozinyl,2,3-dihydro-1,4-benzoxazinyl, 1,3-benzodioxolyl, cyclopropyl,cyclobutyl, azetidinyl, cyclopentyl, cyclohexyl or cycloheptyl ringsystem, said ring system substituted independently with 1-3 substituentsof R¹², R¹³, R¹⁴ or R¹⁶; alternatively, R¹⁰ and R¹¹ taken together forma partially or fully saturated or unsaturated 5-6 membered ring ofcarbon atoms optionally including 1-3 heteroatoms selected from O, N, orS, and the ring optionally substituted independently with 1-3substituents of R¹², R¹³, R¹⁴ or R¹⁶; R¹² is H, C₁₋₁₀-alkyl,C₂₋₁₀-alkenyl, C₂₋₁₀-alkynyl, C₃₋₁₀-cycloalkyl, C₄₋₁₀-cycloalkenyl,C₁₋₁₀-alkylamino-, C₁₋₁₀-dialkylamino-, C₁₋₁₀-alkoxyl orC₁₋₁₀-thioalkyl, each of which is optionally substituted independentlywith 1-3 substituents of R¹³, R¹⁴, R¹⁵ or R¹⁶; R¹³ is NR¹⁴R¹⁵, NR¹⁵R¹⁵,OR¹⁴; SR¹⁴, OR¹⁵; SR¹⁵, C(O)R¹⁴, OC(O)R¹⁴, COOR¹⁴, C(O)R¹⁵, OC(O)R¹⁵,COOR¹⁵, C(O)NR¹⁴R¹⁵, C(O)NR¹⁵R¹⁵, NR¹⁴C(O)R¹⁴, NR¹⁵C(O)R¹⁴, NR¹⁴C(O)R¹⁵,NR¹⁵C(O)R¹⁵, NR¹⁵C(O)NR¹⁴R¹⁵, NR¹⁵C(O)NR¹⁵R¹⁵, NR¹⁵(COOR¹⁴),NR¹⁵(COOR¹⁵), OC(O)NR¹⁴R¹⁵, OC(O)NR¹⁵R¹⁵, S(O)₂R¹⁴, S(O)₂R¹⁵,S(O)₂NR¹⁴R¹⁵, S(O)₂NR¹⁵R¹⁵, NR¹⁴S(O)₂NR¹⁴R¹⁵, NR¹⁵S(O)₂NR¹⁵R¹⁵,NR¹⁴S(O)₂R¹⁴ or NR¹⁵S(O)₂R¹⁵; R¹⁴ is phenyl, pyridyl, pyrimidinyl,thiophenyl, furyl, tetrahydrofuryl, pyrrolyl, pyrazolyl,thieno-pyrazolyl, imidazolyl, triazolyl, thiazolyl, thiadiazolyl,benzothiazolyl, oxazolyl, oxadiazolyl, benzoxazolyl, benzoxadiazolyl,isoxazolyl, isothiazolyl, indolyl, azaindolyl, isoindolyl, indazolyl,benzofuranyl, benzothiophenyl, benzimidazolyl, pyrrolidinyl,pyrazolinyl, morpholinyl, piperidinyl, piperazinyl,2,3-dihydro-1,4-benzoxazinyl, 1,3-benzodioxolyl, cyclopropyl,cyclobutyl, azetidinyl, cyclopentyl and cyclohexyl, each of which isoptionally substituted independently with 1-3 substituents of R¹⁵ orR¹⁶; R¹⁵ is H or C₁₋₁₀-alkyl, C₂₋₁₀-alkenyl, C₂₋₁₀-alkynyl,C₃₋₁₀-cycloalkyl, C₄₋₁₀-cycloalkenyl, C₁₋₁₀-alkylamino-,C₁₋₁₀-dialkylamino-, C₁₋₁₀-alkoxyl or C₁₋₁₀-thioalkoxyl, each of whichis optionally substituted independently with 1-3 substituents of R¹⁶;and R¹⁶ is H, halo, haloalkyl, CN, OH, NO₂, NH₂, OH, methyl, methoxyl,ethyl, ethoxyl, propyl, propoxyl, isopropyl, cyclopropyl, butyl,isobutyl, tert-butyl, methylamino, dimethylamino, ethylamino,diethylamino, isopropylamino, oxo, acetyl, benzyl, phenyl, cyclopropyl,cyclobutyl or a partially or fully saturated or unsaturated 5-8 memberedmonocyclic or 6-12 membered bicyclic ring system, said ring systemformed of carbon atoms optionally including 1-3 heteroatoms ifmonocyclic or 1-6 heteroatoms if bicyclic, said heteroatoms selectedfrom O, N, or S, and optionally substituted independently with 1-5substituents of halo, haloalkyl, CN, NO₂, NH₂, OH, methyl, methoxyl,ethyl, ethoxyl, propyl, propoxyl, isopropyl, cyclopropyl, butyl,isobutyl, tert-butyl, methylamino, dimethylamino, ethylamino,diethylamino, isopropylamino, benzyl or phenyl.
 8. A compound, or apharmaceutically acceptable salt thereof, selected from:3-((2-amino-5-pyrimidinyl)ethynyl)-4-methyl-N-(3-(trifluoromethyl)phenyl)benzamide;6-((2-amino-5-pyrimidinyl)ethynyl)-N-(3-(trifluoromethyl)phenyl)-2-pyridinecarboxamide;5-((2-amino-5-pyrimidinyl)ethynyl)-N-(3-(trifluoromethyl)phenyl)-3-pyridinecarboxamide;2-((2-amino-5-pyrimidinyl)ethynyl)-N-(3-(trifluoromethyl)phenyl)-4-pyridinecarboxamide;5-((2-amino-5-pyrimidinyl)ethynyl)-2-fluoro-N-(3-(trifluoromethyl)phenyl)benzamide;3-((2-amino-5-pyrimidinyl)ethynyl)-4-methyl-N-(2-(4-methyl-1-piperazinyl)-5-(trifluoromethyl)phenyl)benzamide;3-((2-amino-5-pyrimidinyl)ethynyl)-N-(2-((3-(dimethylamino)propyl)(methyl)amino)-5-(trifluoromethyl)phenyl)-4-methylbenzamide;3-((2-amino-5-pyrimidinyl)ethynyl)-N-(2-(dimethylamino)-5-(trifluoromethyl)phenyl)-4-methylbenzamide;3-((2-amino-5-pyrimidinyl)ethynyl)-N-(2-((3R)-3-(dimethylamino)-1-pyrrolidinyl)-5-(trifluoromethyl)phenyl)-4-methylbenzamide;3-((2-amino-5-pyrimidinyl)ethynyl)-4-methyl-N-(2-(methyl(1-methyl-4-piperidinyl)amino)-5-(trifluoromethyl)phenyl)benzamide;3-((2-amino-5-pyrimidinyl)ethynyl)-4-methyl-N-(2-(methyl((3R)-1-methyl-3-pyrrolidinyl)amino)-5-(trifluoromethyl)phenyl)benzamide;3-((2-amino-5-pyrimidinyl)ethynyl)-N-(2-(2-(dimethylamino)-1,1-dimethylethyl)-5-(trifluoromethyl)phenyl)-4-methylbenzamide;3-((2-amino-5-pyrimidinyl)ethynyl)-N-(2-((3S)-3-(dimethylamino)-1-piperidinyl)-5-(trifluoromethyl)phenyl)-4-methylbenzamide;5-((2-amino-5-pyrimidinyl)ethynyl)-2-fluoro-N-(2-(methyl((3S)-1-methyl-3-pyrrolidinyl)amino)-5-(trifluoromethyl)phenyl)benzamide;5-((2-amino-5-pyrimidinyl)ethynyl)-2-fluoro-N-(2-(methyl((3R)-1-methyl-3-pyrrolidinyl)amino)-5-(trifluoromethyl)phenyl)benzamide;5-((2-amino-5-pyrimidinyl)ethynyl)-N-(2-((3-(dimethylamino)propyl)(methyl)amino)-5-(trifluoromethyl)phenyl)-2-fluorobenzamide;5-((2-amino-5-pyrimidinyl)ethynyl)-N-(2-((3R)-3-(dimethylamino)-1-pyrrolidinyl)-5-(trifluoromethyl)phenyl)-2-fluorobenzamide;3-((2-amino-5-pyrimidinyl)ethynyl)-N-(5-cyclohexyl-2-(methyloxy)phenyl)-4-methylbenzamide;5-((2-methyl-5-((6-(trifluoromethyl)-2,3-dihydro-1H-indol-1-yl)carbonyl)phenyl)ethynyl)-2-pyrimidinamine;5-((2-methyl-5-((7-(trifluoromethyl)-3,4-dihydro-1(2H)-quinolinyl)carbonyl)phenyl)ethynyl)-2-pyrimidinamine;3-((2-amino-5-pyrimidinyl)ethynyl)-N-(2-(4-(hydroxymethyl)-1H-imidazol-1-yl)-5-(trifluoromethyl)phenyl)-4-methylbenzamide;5-((2-amino-5-pyrimidinyl)ethynyl)-N-(2-((3-(dimethylamino)propyl)(methyl)amino)-5-(trifluoromethyl)-3-pyridinyl)-2-fluorobenzamide;3-((2-amino-5-pyrimidinyl)ethynyl)-N-(2-((3-(dimethylamino)propyl)(methyl)amino)-5-(trifluoromethyl)-3-pyridinyl)-4-methylbenzamide;3-((2-amino-5-pyrimidinyl)ethynyl)-N-(3-(trifluoromethyl)phenyl)-1H-indole-1-carboxamide;3-((2-amino-5-pyrimidinyl)ethynyl)-4-methyl-N-(3-(1,2,3,6-tetrahydro-4-pyridinyl)-5-(trifluoromethyl)phenyl)benzamide;N-(3-((2-amino-5-pyrimidinyl)ethynyl)-5-(trifluoromethyl)phenyl)-3-(trifluoromethyl)benzamide;3-((2-amino-5-pyrimidinyl)ethynyl)-4-methyl-N-(3-(1-methyl-4-piperidinyl)-5-(trifluoromethyl)phenyl)benzamide;5-((2-amino-5-pyrimidinyl)ethynyl)-N-(3-(trifluoromethyl)phenyl)-2-thiophenecarboxamide;5-((2-amino-5-pyrimidinyl)ethynyl)-N-(2-((3-(dimethylamino)propyl)(methyl)amino)-5-(trifluoromethyl)phenyl)-2-thiophenecarboxamide;3-((2-amino-5-pyrimidinyl)ethynyl)-N-(4-(1,1-dimethylethyl)phenyl)-4-methylbenzamide;3-((2-amino-5-pyrimidinyl)ethynyl)-N-(2-((3-(dimethylamino)propyl)(methyl)amino)-5-(1,1-dimethylethyl)phenyl)-4-methylbenzamide;5-((2-amino-5-pyrimidinyl)ethynyl)-N-(2-((3-(dimethylamino)propyl)(methyl)amino)-5-(1,1-dimethylethyl)phenyl)-2-thiophenecarboxamide;3-((2-amino-5-pyrimidinyl)ethynyl)-N-(3,5-bis(trifluoromethyl)phenyl)-4-methylbenzamide;3-((2-amino-5-pyrimidinyl)ethynyl)-4-chloro-N-(3-(trifluoromethyl)phenyl)benzamide;3-((2-amino-5-pyrimidinyl)ethynyl)-N-(3-chloro-2-((3-(dimethylamino)propyl)(methyl)amino)-5-(trifluoromethyl)phenyl)-4-methylbenzamide;3-((2-amino-5-pyrimidinyl)ethynyl)-4-chloro-N-(3-methyl-4-(1-methylethyl)phenyl)benzamide;3-((2-amino-5-pyrimidinyl)ethynyl)-4-chloro-N-(4-(1,1-dimethylethyl)phenyl)benzamide;3-((2-amino-4-methyl-5-pyrimidinyl)ethynyl)-N-(2-((3-(dimethylamino)propyl)(methyl)amino)-5-(trifluoromethyl)phenyl)-4-methylbenzamide;3-((2-amino-5-pyrimidinyl)ethynyl)-N-(2-(((3-(dimethylamino)propyl)(methyl)amino)sulfonyl)-5-(trifluoromethyl)phenyl)-4-methylbenzamide;5-((2-amino-5-pyrimidinyl)ethynyl)-N-(3-(trifluoromethyl)phenyl)-3-thiophenecarboxamide;5-((2-amino-4-methyl-5-pyrimidinyl)ethynyl)-2-fluoro-N-(2-(methyl((3R)-1-methyl-3-pyrrolidinyl)amino)-5-(trifluoromethyl)phenyl)benzamide;5-((2-amino-4-methyl-5-pyrimidinyl)ethynyl)-2-fluoro-N-(2-(methyl((3S)-1-methyl-3-pyrrolidinyl)amino)-5-(trifluoromethyl)phenyl)benzamide;3-((2-amino-5-pyrimidinyl)ethynyl)-N-(5-chloro-2-((3-(dimethylamino)propyl)(methyl)amino)phenyl)-4-methylbenzamide;3-((2-amino-5-pyrimidinyl)ethynyl)-N-(4-chloro-3-(trifluoromethyl)phenyl)-4-methylbenzamide;3-((2-amino-5-pyrimidinyl)ethynyl)-4-methyl-N-(3-methyl-4-(1-methylethyl)phenyl)benzamide;3-((2-amino-5-pyrimidinyl)ethynyl)-5-fluoro-N-(2-(methyl((3S)-1-methyl-3-pyrrolidinyl)amino)-5-(trifluoromethyl)phenyl)benzamide;3-((2-amino-5-pyrimidinyl)ethynyl)-5-fluoro-N-(2-(methyl((3R)-1-methyl-3-pyrrolidinyl)amino)-5-(trifluoromethyl)phenyl)benzamide;5-((2-amino-5-pyrimidinyl)ethynyl)-2-fluoro-N-(3-((4-methyl-1-piperazinyl)methyl)-5-(trifluoromethyl)phenyl)benzamide;5-((2-amino-5-pyrimidinyl)ethynyl)-2-fluoro-N-(3-((4-methyl-1-piperazinyl)methyl)-5-(trifluoromethyl)phenyl)benzamide;3-((2-amino-5-pyrimidinyl)ethynyl)-4-methyl-N-(3-((4-methyl-1-piperazinyl)methyl)-5-(trifluoromethyl)phenyl)benzamide;3-((2-amino-5-pyrimidinyl)ethynyl)-4-methyl-N-(3-((4-methyl-1-piperazinyl)carbonyl)-5-(trifluoromethyl)phenyl)benzamide;5-((2-amino-5-pyrimidinyl)ethynyl)-2-fluoro-N-(3-((4-methyl-1-piperazinyl)carbonyl)-5-(trifluoromethyl)phenyl)benzamide;3-((2-amino-5-pyrimidinyl)ethynyl)-4-(methyloxy)-N-(2-methyl-3-(trifluoromethyl)phenyl)benzamide;3-((2-amino-5-pyrimidinyl)ethynyl)-4-methyl-N-(2-((4-methyl-1-piperazinyl)sulfonyl)-5-(trifluoromethyl)phenyl)benzamide;5-((2-amino-5-pyrimidinyl)ethynyl)-N-(3-(1-methyl-4-piperidinyl)-5-(trifluoromethyl)phenyl)-3-thiophenecarboxamide;5-((2-amino-5-pyrimidinyl)ethynyl)-N-(3-chloro-2-((3-(dimethylamino)propyl)(methyl)amino)-5-(trifluoromethyl)phenyl)-2-fluorobenzamide;5-((2-amino-5-pyrimidinyl)ethynyl)-N-(2-(((3-(dimethylamino)propyl)(methyl)amino)sulfonyl)-5-(trifluoromethyl)phenyl)-2-fluorobenzamide;5-((2-amino-5-pyrimidinyl)ethynyl)-2-fluoro-N-(2-((4-methyl-1-piperazinyl)sulfonyl)-5-(trifluoromethyl)phenyl)benzamide;3-((2-amino-5-pyrimidinyl)ethynyl)-4-methyl-N-(2-methyl-3-(trifluoromethyl)phenyl)benzamide;3-((2-amino-5-pyrimidinyl)ethynyl)-4-methyl-N-(3-((trifluoromethyl)oxy)phenyl)benzamide;3-((2-amino-5-pyrimidinyl)ethynyl)-4-(methyloxy)-N-(3-((trifluoromethyl)oxy)phenyl)benzamide;5-((2-amino-5-pyrimidinyl)ethynyl)-N-(2-((3-(dimethylamino)propyl)(methyl)amino)-5-(trifluoromethyl)phenyl)-3-thiophenecarboxamide;4-((2-amino-5-pyrimidinyl)ethynyl)-N-(2-((3-(dimethylamino)propyl)(methyl)amino)-5-(trifluoromethyl)phenyl)-2-thiophenecarboxamide;5-((2-amino-5-pyrimidinyl)ethynyl)-N-(3-((1,1-dioxido-4-thiomorpholinyl)carbonyl)-5-(trifluoromethyl)phenyl)-2-fluorobenzamide;5-((2-amino-4-methyl-5-pyrimidinyl)ethynyl)-N-(3-chloro-2-((3-(dimethylamino)propyl)(methyl)amino)-5-(trifluoromethyl)phenyl)-2-fluorobenzamide;5-((2-amino-5-pyrimidinyl)ethynyl)-2-fluoro-N-(2-(1H-1,2,4-triazol-1-yl)-5-(trifluoromethyl)phenyl)benzamide;3-((2-amino-5-pyrimidinyl)ethynyl)-4-methyl-N-((1R)-1-phenylethyl)benzamide;5-((2-amino-5-pyrimidinyl)ethynyl)-N-(2-((dimethylamino)methyl)-5-(trifluoromethyl)phenyl)-2-fluorobenzamide;3-((2-amino-5-pyrimidinyl)ethynyl)-4-methyl-N-(3-methyl-5-isoxazolyl)benzamide;5-((2-amino-5-pyrimidinyl)ethynyl)-N-(5-cyclopropyl-2-((3-(dimethylamino)propyl)(methyl)amino)phenyl)-2-fluorobenzamide;5-((2-amino-5-pyrimidinyl)ethynyl)-N-(3-((((2S)-1-methyl-2-pyrrolidinyl)methyl)oxy)-5-(trifluoromethyl)phenyl)-3-thiophenecarboxamide;3-((2-amino-5-pyrimidinyl)ethynyl)-4-methyl-N-((1S)-1-(1,3-thiazol-2-yl)ethyl)benzamide;3-((2-amino-5-pyrimidinyl)ethynyl)-4-methyl-N-((1R)-1-(1,3-thiazol-2-yl)ethyl)benzamide;3-((2-amino-5-pyrimidinyl)ethynyl)-N-(3-methyl-5-isoxazolyl)-4-(methyloxy)benzamide;3-((2-amino-5-pyrimidinyl)ethynyl)-4-methyl-N-(2-(4-thiomorpholinyl)-5-(trifluoromethyl)phenyl)benzamide;3-((2-amino-5-pyrimidinyl)ethynyl)-N-(3,4-dimethyl-5-isoxazolyl)-4-methylbenzamide;3-((2-amino-5-pyrimidinyl)ethynyl)-N-(3,4-dimethyl-5-isoxazolyl)-4-(methyloxy)benzamide;3-((2-amino-5-pyrimidinyl)ethynyl)-4-(methyloxy)-N-(3-(1-methyl-4-piperidinyl)-5-(trifluoromethyl)phenyl)benzamide;5-((2-amino-5-pyrimidinyl)ethynyl)-2-fluoro-N-(2-(methyl((3S)-1-methyl-3-pyrrolidinyl)amino)-5-(trifluoromethyl)phenyl)benzamide;5-((2-amino-5-pyrimidinyl)ethynyl)-2-fluoro-N-(2-(methyl((3R)-1-methyl-3-pyrrolidinyl)amino)-5-(trifluoromethyl)phenyl)benzamide;3-((2-amino-5-pyrimidinyl)ethynyl)-4-methyl-N-(3-(4-methyl-1-piperazinyl)-5-(trifluoromethyl)phenyl)benzamide;5-((2-amino-5-pyrimidinyl)ethynyl)-2-(methyloxy)-N-(3-((4-methyl-1-piperazinyl)methyl)-5-(trifluoromethyl)phenyl)benzamide;N-(4-((2-amino-5-pyrimidinyl)ethynyl)-3-methylphenyl)-N′-(3-(trifluoromethyl)phenyl)urea;N-(4-((2-amino-5-pyrimidinyl)ethynyl)-3-methylphenyl)-N′-(3-fluorophenyl)urea;N-(4-((2-amino-5-pyrimidinyl)ethynyl)-3-methylphenyl)-3-(trifluoromethyl)benzamide;N-(4-((2-amino-5-pyrimidinyl)ethynyl)-3-methylphenyl)-4-(trifluoromethyl)benzamide;5-((2-amino-5-pyrimidinyl)ethynyl)-N-(2-((3-(dimethylamino)propyl)(methyl)amino)-5-(trifluoromethyl)phenyl)-2,3-dihydro-1-benzofuran-7-carboxamide;5-((2-amino-5-pyrimidinyl)ethynyl)-N-(2-(methyl((3R)-1-methyl-3-pyrrolidinyl)amino)-5-(trifluoromethyl)phenyl)-2-(methyloxy)benzamide;N-(4-((2-amino-5-pyrimidinyl)ethynyl)phenyl)-3-(trifluoromethyl)benzamide;N-(4-((2-amino-5-pyrimidinyl)ethynyl)phenyl)-1H-benzimidazol-2-amine;5-((2-amino-5-pyrimidinyl)ethynyl)-N-(2-((3S)-3-(dimethylamino)-1-piperidinyl)-5-(trifluoromethyl)phenyl)-2-fluorobenzamide;N-(4-((2-amino-5-pyrimidinyl)ethynyl)-1-naphthalenyl)-1H-benzimidazol-2-amine;5-((2-amino-5-pyrimidinyl)ethynyl)-N-(2-(4-(dimethylamino)-1-piperidinyl)-5-(trifluoromethyl)phenyl)-2-fluorobenzamide;5-((2-amino-5-pyrimidinyl)ethynyl)-2-fluoro-N-(2-(1-piperidinyl)-5-(trifluoromethyl)phenyl)benzamide;5-((2-amino-5-pyrimidinyl)ethynyl)-2-fluoro-N-(2-(2-oxo-1-pyrrolidinyl)-5-(trifluoromethyl)phenyl)benzamide;5-((2-amino-5-pyrimidinyl)ethynyl)-2-(methyloxy)-N-(2-(1-piperidinyl)-5-(trifluoromethyl)phenyl)benzamide;2-fluoro-5-((2-(methylamino)-5-pyrimidinyl)ethynyl)-N-(2-(methyl((3R)-1-methyl-3-pyrrolidinyl)amino)-5-(trifluoromethyl)phenyl)benzamide;5-((2-amino-5-pyrimidinyl)ethynyl)-2-fluoro-N-(2-(4-methyl-1-piperazinyl)-5-(trifluoromethyl)phenyl)benzamide;5-((2-amino-5-pyrimidinyl)ethynyl)-2-fluoro-N-(2-(2-oxo-1,3-oxazolidin-3-yl)-5-(trifluoromethyl)phenyl)benzamide;5-((2-amino-5-pyrimidinyl)ethynyl)-2-fluoro-N-(2-(3-methyl-2-oxo-1-imidazolidinyl)-5-(trifluoromethyl)phenyl)benzamide;5-((2-amino-5-pyrimidinyl)ethynyl)-N-(2-((3R)-3-(dimethylamino)-1-piperidinyl)-5-(trifluoromethyl)phenyl)-2-fluorobenzamide;5-((2-amino-5-pyrimidinyl)ethynyl)-2-fluoro-N-(2-((3S)-3-(methylamino)-1-piperidinyl)-5-(trifluoromethyl)phenyl)benzamide;N-(2-((3S)-3-amino-1-piperidinyl)-5-(trifluoromethyl)phenyl)-5-((2-amino-5-pyrimidinyl)ethynyl)-2-fluorobenzamide;5-((2-amino-5-pyrimidinyl)ethynyl)-2-fluoro-N-(2-(3-oxo-1-piperazinyl)-5-(trifluoromethyl)phenyl)benzamide;5-((2-amino-5-pyrimidinyl)ethynyl)-N-(2-((3R)-3-((dimethylamino)methyl)-1-pyrrolidinyl)-5-(trifluoromethyl)phenyl)-2-fluorobenzamide;5-((2-amino-5-pyrimidinyl)ethynyl)-2-fluoro-N-(2-((3R)-3-hydroxy-1-piperidinyl)-5-(trifluoromethyl)phenyl)benzamide;4-((2-(ethyloxy)phenyl)oxy)-5-(phenylethynyl)-N-(4-((2-(1-pyrrolidinyl)ethyl)oxy)phenyl)-2-pyrimidinamine;5-((2,6-dimethylphenyl)ethynyl)-4-((2-(ethyloxy)phenyl)oxy)-N-(4-((2-(1-pyrrolidinyl)ethyl)oxy)phenyl)-2-pyrimidinamine;5-((2,6-dimethylphenyl)ethynyl)-4-((2-(ethyloxy)phenyl)oxy)-N-(4-(4-methyl-1-piperazinyl)phenyl)-2-pyrimidinamine;3-((2-amino-5-pyrimidinyl)ethynyl)-N-(4-((2-(dimethylamino)ethyl)oxy)phenyl)-4-methylbenzamide;3-((2-amino-5-pyrimidinyl)ethynyl)-4-methyl-N-(4-(trifluoromethyl)-2-pyridinyl)benzamide;3-((2-amino-5-pyrimidinyl)ethynyl)-N-(2-fluoro-5-(trifluoromethyl)phenyl)-4-methylbenzamide;3-((2-amino-5-pyrimidinyl)ethynyl)-4-methyl-N-(2-(methyloxy)-5-(trifluoromethyl)phenyl)benzamide;3-((2-amino-5-pyrimidinyl)ethynyl)-N-(4-ethyl-2-pyridinyl)-4-methylbenzamide;4-methyl-3-((2-((2-(4-morpholinyl)ethyl)amino)-5-pyrimidinyl)ethynyl)-N-(3-(trifluoromethyl)phenyl)benzamide;4-((2-amino-5-pyrimidinyl)ethynyl)-N-(2-fluoro-5-(trifluoromethyl)phenyl)-3-methylbenzamide;4-methyl-3-((2-((4-(4-methyl-1-piperazinyl)phenyl)amino)-5-pyrimidinyl)ethynyl)-N-(3-(trifluoromethyl)phenyl)benzamide;3-((2-amino-5-pyrimidinyl)ethynyl)-4-methyl-N-(4-(4-(1-methylethyl)-1-piperazinyl)phenyl)benzamide;3-((2-amino-5-pyrimidinyl)ethynyl)-N-(4-(1,1-dimethylethyl)-3-((N,N-dimethylglycyl)amino)phenyl)-4-methylbenzamide;3-((2-amino-5-pyrimidinyl)ethynyl)-N-(5,5-dimethyl-3-oxo-1-cyclohexen-1-yl)-4-methylbenzamide;3-((2-amino-5-pyrimidinyl)ethynyl)-N-(3-(1,1-dimethylethyl)-1-methyl-1H-pyrazol-5-yl)-4-methylbenzamide;3-((2-amino-5-pyrimidinyl)ethynyl)-N-(5-(1,1-dimethylethyl)-2-(methyloxy)phenyl)-4-methylbenzamide;3-((2-amino-5-pyrimidinyl)ethynyl)-N-(3-((dimethylamino)methyl)-5-(trifluoromethyl)phenyl)-4-methylbenzamide;4-((2-amino-5-pyrimidinyl)ethynyl)-3-methyl-N-(3-((4-methyl-1-piperazinyl)methyl)-5-(trifluoromethyl)phenyl)benzamide;3-((2-amino-5-pyrimidinyl)ethynyl)-4-methyl-N-(3-(2-oxo-1-pyrrolidinyl)-5-(trifluoromethyl)phenyl)benzamide;N-(3-((2-amino-5-pyrimidinyl)ethynyl)-2-methylphenyl)-3-(trifluoromethyl)benzamide;3-((2-amino-5-pyrimidinyl)ethynyl)-4-methyl-N-(3-(1-pyrrolidinylmethyl)-5-(trifluoromethyl)phenyl)benzamide;3-((2-amino-5-pyrimidinyl)ethynyl)-4-methyl-N-(3-(4-morpholinylmethyl)-5-(trifluoromethyl)phenyl)benzamide;3-((2-amino-4-methyl-5-pyrimidinyl)ethynyl)-4-methyl-N-(3-((4-methyl-1-piperazinyl)methyl)-5-(trifluoromethyl)phenyl)benzamide;3-((2-amino-5-pyrimidinyl)ethynyl)-4-methyl-N-(2-(2-oxo-1-pyrrolidinyl)-5-(trifluoromethyl)phenyl)benzamide;3-((2-amino-5-pyrimidinyl)ethynyl)-4-methyl-N-(2-(2-oxo-1,3-oxazolidin-3-yl)-5-(trifluoromethyl)phenyl)benzamide;3-((2-amino-5-pyrimidinyl)ethynyl)-N-(4-cyano-2-pyridinyl)-4-methylbenzamide;3-((2-amino-5-pyrimidinyl)ethynyl)-4-methyl-N-(3-(3-(4-morpholinyl)propyl)-5-(trifluoromethyl)phenyl)benzamide;4-methyl-3-((2-(methylamino)-5-pyrimidinyl)ethynyl)-N-(3-((4-methyl-1-piperazinyl)methyl)-5-(trifluoromethyl)phenyl)benzamide;3-((2-amino-5-pyrimidinyl)ethynyl)-4-methyl-N-(3-(3-(4-methyl-1-piperazinyl)propyl)-5-(trifluoromethyl)phenyl)benzamide;3-((2-amino-5-pyrimidinyl)ethynyl)-N-(3-(3-(dimethylamino)-1-propyn-1-yl)-5-(trifluoromethyl)phenyl)-4-methylbenzamide;3-((2-amino-5-pyrimidinyl)ethynyl)-N-(2-(3-(dimethylamino)-1-propyn-1-yl)-5-(trifluoromethyl)phenyl)-4-methylbenzamide;N-(3-((2-amino-5-pyrimidinyl)ethynyl)-4-methylphenyl)-3-(trifluoromethyl)benzamide;4-methyl-N-(3-((4-methyl-1-piperazinyl)methyl)-5-(trifluoromethyl)phenyl)-3-(3-pyridinylethynyl)benzamide;4-methyl-3-((2-(methylamino)-5-pyrimidinyl)ethynyl)-N-(3-(1-methyl-4-piperidinyl)-5-(trifluoromethyl)phenyl)benzamide;4-methyl-N-(2-(2-oxo-1-pyrrolidinyl)-5-(trifluoromethyl)phenyl)-3-(3-pyridinylethynyl)benzamide;4-methyl-3-((2-(methylamino)-4-(2-thienyl)-5-pyrimidinyl)ethynyl)-N-(3-((4-methyl-1-piperazinyl)methyl)-5-(trifluoromethyl)phenyl)benzamide;4-methyl-3-((2-((1-methylethyl)amino)-5-pyrimidinyl)ethynyl)-N-(3-((4-methyl-1-piperazinyl)methyl)-5-(trifluoromethyl)phenyl)benzamide;4-((2-amino-5-pyrimidinyl)ethynyl)-N-(2-(methyl((3R)-1-methyl-3-pyrrolidinyl)amino)-5-(trifluoromethyl)phenyl)-1-(methyloxy)-2-naphthalenecarboxamide;4-methyl-3-((4-((2-(methyloxy)phenyl)oxy)-2-((4-(4-methyl-1-piperazinyl)phenyl)amino)-5-pyrimidinyl)ethynyl)-N-(3-(trifluoromethyl)phenyl)benzamide;4-((2-(methyloxy)phenyl)oxy)-N-(4-(4-methyl-1-piperazinyl)phenyl)-5-(phenylethynyl)-2-pyrimidinamine;N-(3-methyl-4-((4-((2-(methyloxy)phenyl)oxy)-2-((4-(4-methyl-1-piperazinyl)phenyl)amino)-5-pyrimidinyl)ethynyl)phenyl)-N′-(3-(trifluoromethyl)phenyl)urea;5-((2-amino-5-pyrimidinyl)ethynyl)-N-(2-(3,3-dimethyl-2-oxo-1-azetidinyl)-5-(trifluoromethyl)phenyl)-2-(methyloxy)benzamide;5-((2-amino-5-pyrimidinyl)ethynyl)-2-fluoro-N-(2-(4-thiomorpholinyl)-5-(trifluoromethyl)phenyl)benzamide;5-((2-amino-5-pyrimidinyl)ethynyl)-2-fluoro-N-(2-(methyl(1-methyl-4-piperidinyl)amino)-5-(trifluoromethyl)phenyl)benzamide;5-((2-amino-5-pyrimidinyl)ethynyl)-2-fluoro-N-(2-((4-methyl-1-piperazinyl)methyl)-5-(trifluoromethyl)phenyl)benzamide;5-((2-amino-5-pyrimidinyl)ethynyl)-2-fluoro-N-(2-(4-morpholinyl)-5-(trifluoromethyl)phenyl)benzamide;5-((2-amino-5-pyrimidinyl)ethynyl)-N-(2-((3S)-3-(dimethylamino)-1-pyrrolidinyl)-5-(trifluoromethyl)phenyl)-2-fluorobenzamide;5-((2-amino-5-pyrimidinyl)ethynyl)-2-fluoro-N-(2-((2-(4-morpholinyl)ethyl)oxy)-5-(trifluoromethyl)phenyl)benzamide;5-((2-amino-5-pyrimidinyl)ethynyl)-2-fluoro-N-(2-((1S,4R)-5-methyl-2,5-diazabicyclo[2.2.1]hept-2-yl)-5-(trifluoromethyl)phenyl)benzamide;5-((2-amino-5-pyrimidinyl)ethynyl)-2-fluoro-N-(2-((2-(1-pyrrolidinyl)ethyl)oxy)-5-(trifluoromethyl)phenyl)benzamide;5-((2-amino-5-pyrimidinyl)ethynyl)-N-(2-(((3S)-1-ethyl-3-pyrrolidinyl)oxy)-5-(trifluoromethyl)phenyl)-2-fluorobenzamide;5-((2-amino-5-pyrimidinyl)ethynyl)-N-(2-(((3S)-1-ethyl-3-piperidinyl)oxy)-5-(trifluoromethyl)phenyl)-2-fluorobenzamide;N-(2-((3S)-3-(dimethylamino)-1-piperidinyl)-5-(trifluoromethyl)phenyl)-2-fluoro-5-((2-(methylamino)-5-pyrimidinyl)ethynyl)benzamide;5-((2-amino-4-methyl-5-pyrimidinyl)ethynyl)-N-(2-((3S)-3-(dimethylamino)-1-piperidinyl)-5-(trifluoromethyl)phenyl)-2-fluorobenzamide;N-cyclopropyl-4-methyl-3-((2-((2-(4-morpholinyl)ethyl)amino)-5-pyrimidinyl)ethynyl)benzamide;N-(4-((2-((4-(4-methyl-1-piperazinyl)phenyl)amino)-5-pyrimidinyl)ethynyl)phenyl)-1H-benzimidazol-2-amine;N-(4-((2-((4-(4-methyl-1-piperazinyl)phenyl)amino)-5-pyrimidinyl)ethynyl)phenyl)-3-(trifluoromethyl)benzamide;4-((2-((4-(4-methyl-1-piperazinyl)phenyl)amino)-5-pyrimidinyl)ethynyl)-N-(3-(trifluoromethyl)phenyl)benzamide;andN-(4-((2-amino-5-pyrimidinyl)ethynyl)phenyl)-2-(phenylamino)benzamide.9. A pharmaceutical composition comprising a pharmaceutically acceptablecarrier and a compound according to claim
 1. 10. A pharmaceuticalcomposition comprising a pharmaceutically acceptable carrier and acompound according to claim
 8. 11. A method of treating a rheumatoidarthritis in a subject, the method comprising administering to thesubject an effective dosage amount of a compound of claim
 1. 12. Amethod of treating breast cancer in a subject, the method comprisingadministering to the subject an effective dosage amount of a compoundaccording to claim
 1. 13. A method of treating breast cancer in asubject, the method comprising administering to the subject an effectivedosage amount of the pharmaceutical composition according to claim 9.14. A method of reducing blood flow in a tumor selected from breastcancer, colon carcinoma and thymoma in a subject, said method comprisingadministering to the subject an effective dosage amount of a compoundaccording to claim
 1. 15. A method of treating colon carcinoma orthymoma in a subject, the method comprising administering to the subjectan effective dosage amount of a compound according to claim 1.